Pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient

ABSTRACT

A pyridonecarboxylic acid derivative represented by the following general formula (1): ##STR1## [wherein R 1  represents hydrogen atom or a carboxyl protective group; R 2  represents hydroxyl group, a lower alkoxy group, or a substituted or unsubstituted amino group; R 3  represents hydrogen atom or a halogen atom; R 4  represents hydrogen atom or a halogen atom; R 5  represents a halogen atom or an optionally substituted saturated cyclic amino group; R 6  represents hydrogen atom, a halogen atom, nitro group, or an optionally protected amino group; X, Y and Z may be the same or different and respectively represent nitrogen atom, --CH═ or --CR 7  ═ (wherein R 7  represents a lower alkyl group, a halogen atom, or cyano group) (with the proviso that at least one of X, Y and Z represent the nitrogen atom), and W represents nitrogen atom or --CR 8  ═ (wherein R 8  represents hydrogen atom, a halogen atom, or a lower alkyl group)] or its salt, as well as an antibacterial agent containing such compound are provided.

This application claims the benefit under 35 U.S.C. §371 of prior PCTInternational Application No. PCT/JP96/02710, which has an Internationalfiling date of Sep. 20, 1996, which designated the United States ofAmerica, the entire contents of which are hereby incorporated byreferences.

TECHNICAL FIELD

The present invention relates to novel pyridonecarboxylic acidderivatives or salts thereof having excellent antibacterial propertiesand oral absorption, and antibacterial agents containing the same.

BACKGROUND ART

Many compounds having basic skeleton of pyridonecarboxylic acid areknown to be useful synthetic antibacterials for their excellentantibacterial properties and wide antibacterial spectrum. Among suchcompounds, norfloxacin (Japanese Patent Application Laid-Open No.53-141286), enoxacin (Japanese Patent Application Laid-Open No.55-31042), ofloxacin (Japanese Patent Application Laid-Open No.57-46986), ciprofloxacin (Japanese Patent Application Laid-Open No.58-76667), tosufloxacin (Japanese Patent Application Laid-Open No.60-228479), and the like are widely used in clinical practice fortreating infections.

These compounds, however, need further improvements in antibacterialactivities, intestinal absorption, metabolic stability, and sideeffects, and in particular, in phototoxicity, cytotoxicity.

Accordingly, an object of the present invention is to provide novelcompounds which are sufficient in such aspects.

DISCLOSURE OF THE INVENTION

In view of such situation, the inventors of the present invention havemade an intensive study to find compounds which would be excellentsynthetic antibacterial agents in clinical practice, and found thatnovel compounds represented by the following general formula (1) hasgood antibacterial properties to gram negative and positive bacteria aswell as an extremely low toxicity, and therefore, would be a very usefulsynthetic antibacterial. The present invention has been accomplished onthe bases of such a finding. ##STR2## [In the formula, R¹ representshydrogen atom or a carboxyl protective group; R² represents hydroxylgroup, a lower alkoxy group, or a substituted or unsubstituted aminogroup; R³ represents hydrogen atom or a halogen atom; R⁴ representshydrogen atom or a halogen atom; R⁵ represents a halogen atom or anoptionally substituted saturated cyclic amino group; R⁶ representshydrogen atom, a halogen atom, nitro group, or an optionally protectedamino group; X, Y and Z may be the same or different and respectivelyrepresent nitrogen atom, --CH═ or --CR⁷ ═ (wherein R⁷ represents a loweralkyl group, a halogen atom, or cyano group) (with the proviso that atleast one of X, Y and Z represents the nitrogen atom), and W representsnitrogen atom or --CR⁸ ═ (wherein R⁸ represents hydrogen atom, a halogenatom, or a lower alkyl group.)]

Accordingly, the present invention provides pyridonecarboxylic acidderivatives represented by the general formula (1), above, or theirsalts, and antibacterial agents containing the pyridonecarboxylic acidderivatives or their pharmaceutically acceptable salts as theireffective components.

BEST MODE FOR CARRYING OUT THE INVENTION

The novel pyridonecarboxylic acid derivatives of the present inventionare represented by the general formula (1) as shown above, and the term"lower" used for the substituents of the pyridonecarboxylic acidderivatives represented by the general formula (1) designates that thesubstituent comprises 1 to 7 carbon atoms, and preferably 1 to 5 carbonatoms in the case of a linear substituent, and that the substituentcomprises 3 to 7 carbon atoms in the case of a cyclic substituent.

In the general formula (1), R¹ represents hydrogen atom or acarboxyl-protective group, and the term, carboxyl-protective groupherein designates an ester residue of a carboxylate ester, and thecarboxyl protective group may be any carboxylate ester residue whichcleaves relatively easily to generate the corresponding free carboxylgroup. Exemplary carboxyl protective groups include those which may beeliminated by hydrolysis, catalytic reduction, and other treatmentsunder mild conditions such as lower alkyl groups such as methyl group,ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butylgroup, t-butyl group, pentyl group, hexyl group, and heptyl group; loweralkenyl groups such as vinyl group, allyl group, 1-propenyl group,butenyl group, pentenyl group, hexenyl group, and heptenyl group;aralkyl groups such as benzyl group; and aryl groups such as phenylgroup and naphthyl group; and those which may be readily eliminated inthe body such as lower alkanoyloxy lower alkyl groups such asacetoxymethyl group and pivaloyloxymethyl group; lower alkoxycarbonyloxylower alkyl group such as methoxycarbonyloxymethyl group and1-ethoxycarbonyloxyethyl group; lower alkoxymethyl group such asmethoxymethyl group; lactonyl group such as phthalidyl; di-loweralkylamino lower alkyl group such as 1-dimethylaminoethyl group; and(5-methyl-2-oxo-1,3-dioxole-4-yl)methyl group. It should be noted thatR¹ is most preferably hydrogen atom.

In the general formula (1), R² represents hydroxyl group, a lower alkoxygroup, or a substituted or unsubstituted amino group. Exemplarysubstituents for the substituted amino group include lower alkyl groupssuch as methyl group, ethyl group, n-propyl group, i-propyl group,n-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group,and heptyl group; lower alkenyl groups such as vinyl group, allyl group,1-propenyl group, butenyl group, pentenyl group, hexenyl group, andheptenyl group; aralkyl groups such as benzyl group and 1-phenylethyl;aryl groups such as phenyl group and naphthyl group; lower alkanoylgroups such as formyl group, acetyl group, propionyl group, butylylgroup, and isobutylyl group; lower alkoxycarbonyl groups such asmethoxycarbonyl group and ethoxycarbonyl group; aroyl groups such asbenzoyl group and naphthoyl group; amino acid residues or oligopeptideresidues such as glycyl, leucyl, valyl, alanyl, phenylalanyl,alanyl--alanyl, glycyl-valyl, and glycyl--glycyl-valyl, and the aminoacid residues or the oligopeptide residues wherein the functional groupthereof is protected with an acyl, a lower aralkyl, or other protectivegroups which is commonly used in peptide chemistry; and cyclic aminogroup. One or two substituents which may be the same or different may beselected from the substituents as described above. The compoundprotected with the amino acid residue or the oligopeptide residue isexpected to have an improved water solubility.

Preferably, R² is amino group, a lower alkylamino group, a di-loweralkylamino group, a lower alkanoylamino group, an amino acid-substitutedamino group, or an oligopeptide-substituted amino group. More preferableexamples of R² include amino group, methylamino group, ethylamino group,and dimethylamino group, among which the amino group being the mostpreferred. It should be noted that the exemplary preferable lower alkoxygroups used for R² include lower alkoxy groups having 1 to 4 carbonatoms such as methoxy group, ethoxy group, propoxy group, and butoxygroup, and among these, use of methoxy group is preferable.

Next, in the general formula (1), R³ represents hydrogen atom or ahalogen atom; R⁴ represents hydrogen atom or a halogen atom; R⁵represents a halogen atom or an optionally substituted saturated cyclicamino group; R⁶ represents hydrogen atom, a halogen atom, nitro group,or an optionally protected amino group; X, Y and Z may be the same ordifferent and respectively represent nitrogen atom, --CH═ or --CR⁷ ═(wherein R⁷ represents a lower alkyl group, a halogen atom, or cyanogroup), and W represents nitrogen atom or --CR⁸ ═ (wherein R⁸ representshydrogen atom or a halogen atom).

The halogen atoms represented by R³, R⁴, R⁵, R⁶, R⁷ and R⁸ includefluorine atom, chlorine atom, bromine atom and iodine atom. Among these,fluorine atom and chlorine atom are the preferred, and in particular, R³to R⁷ are preferably fluorine atom and R⁸ is preferably chlorine atom orbromine atom.

The lower alkyl groups represented by R⁷ and R⁸ include those containing1 to 7 carbon atoms such as methyl group, ethyl group, propyl group,butyl group, pentyl group, hexyl group, and heptyl group, among whichmethyl group is the preferred.

With regard to X, Y and Z, two or three of X, Y and Z may be the same,or alternatively, they may be different from each other. It is, however,required that at least one of X, Y and Z is nitrogen atom. Exemplarypreferable combinations of X, Y and Z are nitrogen for X and --CH═ or--CR⁷ ═ (wherein R⁷ represents a lower alkyl group, a halogen atom orcyano group) for Y and Z; nitrogen for Y and --CH═ or --CR⁷ ═ (whereinR⁷ represents a lower alkyl group or a halogen atom) for X and Z; andnitrogen for X and Y, and --CH═ or --CR⁷ ═ (wherein R⁷ represents alower alkyl group or a halogen atom) for Z.

It should be also noted that the compound of formula (1) hasnaphthylidine skeleton when W represents nitrogen, and quinolineskeleton when W represents --CR⁸ ═, and it is most preferable that Wrepresents --CR⁸ ═ (wherein R⁸ represents a halogen atom or a loweralkyl group).

Next, the optionally substituted saturated cyclic amino grouprepresented by the R⁵ may additionally contain 1 or more heteroatomssuch as nitrogen atom, oxygen atom, and sulfur atom as well as carbonylcarbon in its ring, and may be either monocyclic, or bi- or tricyclic.The saturated cyclic amino group is preferably a 4 to 7-membered ringwhen it is monocyclic, a 7 to 11-membered ring when it is bicyclic, and9 to 15-membered ring when it is tricyclic. Exemplary such cyclic aminogroups include saturated monocyclic amino groups of 3 to 7-membered ringcontaining one nitrogen atom such as aziridin-1-yl, azetidin-1-yl,pyrrolidin-1-yl, and piperidin-1-yl; saturated monocyclic amino groupsof 3 to 7-membered ring containing two nitrogen atoms such aspiperazin-1-yl and homopiperazin-1-yl; saturated monocyclic amino groupsof 3 to 7-membered ring containing a heteroatom selected from oxygenatom and sulfur atom in addition to nitrogen atom such asoxazolidin-3-yl, morpholin-4-yl, thiazolidin-1-yl, andthiomorpholin-4-yl; saturated bi- or tricyclic amino groups such astetrahydroquinolin-1-yl; and spiro or cross-linked saturated aminogroups of 5 to 12-membered ring such as 2,8-diazaspiro[4.4]nonan-2-yl,5-azaspiro[2.4]heptan-5-yl, 7-azabicyclo[2.2.1]heptan-7-yl,2,8-diazabicyclo[4.3.0]nonan-8-yl,5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl,2,5-diazabicyclo[2.2.1]heptan-2-yl, and3,8-diazabicyclo[3.2.1]octan-3-yl.

The atom constituting the ring of such saturated cyclic amino group maybe substituted with an appropriate substituent, and exemplary suchsubstituents include hydroxyl group, lower alkyl groups, substituted andunsubstituted amino groups, substituted and unsubstituted amino loweralkyl groups, lower alkoxy groups, and halogen atoms.

Exemplary lower alkyl groups for the substituent of the saturated cyclicamino group include those containing 1 to 7 carbon atoms such as methylgroup, ethyl group, propyl group, butyl group, pentyl group, hexylgroup, and heptyl group; and exemplary lower alkoxy groups include thosecontaining 1 to 7 carbon atoms such as methoxy group, ethoxy group, andn-propoxy group; and exemplary halogen groups include fluorine atom,chlorine atom, and bromine atom. Of the substituents of the saturatedcyclic amino groups, the substituted amino groups and substituted aminolower alkyl groups may have a substituent which may be the same as thosedescribed for R², and preferable examples of the substituted aminogroups and the substituted and unsubstituted amino lower alkyl groupsinclude methylamino group, ethylamino group, dimethylamino group,aminomethyl group, 1-aminoethyl group, 2-aminoethyl group,1-amino-1-ethyl group, methylaminomethyl group, ethylaminomethyl group,dimethylaminomethyl group, glycyl-amino group, leucyl-amino group,valyl-amino group, alanyl-amino group, and alanyl--alanyl-amino group.

Of the saturated cyclic amino groups as described above, the mostpreferable group for R⁵ include those represented by the followingformulae (a) and (b): ##STR3## [wherein A represents oxygen atom, sulfuratom or NR⁹ (wherein R⁹ represents hydrogen atom or a lower alkylgroup), e represents a number of from 3 to 5, f represents a number offrom 1 to 3, g represents a number of from 0 to 2, J¹, J² and J³, whichmay be the same or different, represent hydrogen atom, hydroxyl group, alower alkyl group, an amino lower alkyl group, amino group, a loweralkylamino group, a lower alkoxy group, or a halogen atom.]

Examples of the lower alkyl group, the amino lower alkyl group, thelower alkylamino group, the lower alkoxy group, and the halogen atom inthe formulae (a) and (b) as described above are the same as those shownfor R² to R⁵.

Exemplary cyclic amino groups represented by the formula (a) includeazetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, and exemplary cyclicamino groups represented by the formula (b) include piperazin-1-yl,morpholin-4-yl, thiomorpholin-4-yl, homopiperazin-1-yl, N-thiazolidinyl,and N-oxazolidinyl. When R⁵ is a cyclic amino group, R⁵ is preferablythe cyclic amino group represented by formula (a), and R⁵ is mostpreferably azetidin-1-yl or pyrrolidin-1-yl.

The most preferable examples of the groups represented by the formulae(a) and (b) are as described below.

3-aminoazetidin-1-yl group, 3-methylaminoazetidin-1-yl group,

3-dimethylaminoazetidin-1-yl group,

3-aminomethylazetidin-1-yl group,

3-amino-2-methylazetidin-1-yl group,

3-amino-3-methylazetidin-1-yl group,

3-alanyl-aminoazetidin-1-yl group,

3-valyl-aminoazetidin-1-yl group, 3-pyrrolidin-1-yl group,

3-hydroxypyrrolidin-1-yl group,

3,4-dihydroxypyrrolidin-1-yl group,

3-methoxypyrrolidin-1-yl group,

3-methylpyrrolidin-1-yl group,

3-hydroxy-4-methylpyrrolidin-1-yl group,

3-aminopyrrolidin-1-yl group,

3-methylaminopyrrolidin-1-yl group,

3-dimethylaminopyrrolidin-1-yl group,

3-ethylaminopyrrolidin-1-yl group,

3-diethylaminopyrrolidin-1-yl group,

3-aminomethylpyrrolidin-1-yl group,

3-amino-3-methylpyrrolidin-1-yl group,

3-amino-4-methylpyrrolidin-1-yl group,

3-amino-5-methylpyrrolidin-1-yl group,

3-methylamino-4-methylpyrrolidin-1-yl group,

3-dimethylamino-4-methylpyrrolidin-1-yl group,

3-ethylamino-4-methylpyrrolidin-1-yl group,

3-diethylamino-3-methylpyrrolidin-1-yl group,

3-diethylamino-4-methylpyrrolidin-1-yl group,

3-aminomethyl-4-methylpyrrolidin-1-yl group,

3-methylaminomethyl-4-methylpyrrolidin-1-yl group,

3-dimethylaminomethyl-4-methylpyrrolidin-1-yl group,

3-ethylaminomethyl-4-methylpyrrolidin-1-yl group,

3-(1-aminoethyl)-4-methylpyrrolidin-1-yl group,

3-(2-aminoethyl)-4-methylpyrrolidin-1-yl group,

3-amino-4-ethylpyrrolidin-1-yl group,

3-methylamino-4-ethylpyrrolidin-1-yl group,

3-dimethylamino-4-ethylpyrrolidin-1-yl group,

3-ethylamino-4-ethylpyrrolidin-1-yl group,

3-diethylamino-4-ethylpyrrolidin-1-yl group,

3-aminomethyl-4-ethylpyrrolidin-1-yl group,

3-methylaminomethyl-4-ethylpyrrolidin-1-yl group,

3-dimethylaminomethyl-4-ethylpyrrolidin-1-yl group,

3-amino-3-methylpyrrolidin-1-yl group,

3-methylamino-3-methylpyrrolidin-1-yl group,

3-dimethylamino-3-methylpyrrolidin-1-yl group,

3-amino-3,4-dimethylpyrrolidin-1-yl group,

3-amino-4,4-dimethylpyrrolidin-1-yl group,

3-amino-4,5-dimethylpyrrolidin-1-yl group,

3-amino-2,4-dimethylpyrrolidin-1-yl group,

3-methylamino-3,4-dimethylpyrrolidin-1-yl group,

2-methyl-3-aminopyrrolidin-1-yl group,

2-methyl-3-dimethylaminopyrrolidin-1-yl group,

3-amino-4-methoxypyrrolidin-1-yl group,

3-alanyl-aminopyrrolidin-1-yl group,

3-valyl-aminopyrrolidin-1-yl group, piperazin-1-yl group,

4-methylpiperazin-1-yl group, 3-methylpiperazin-1-yl group,

2-methylpiperazin-1-yl group, 3,4-dimethylpiperazin-1-yl group,3,5-dimethylpiperazin-1-yl group,

3,3-dimethylpiperazin-1-yl group,

3,4,5-trimethylpiperazin-1-yl group, piperidin-1-yl group,

4-aminopiperidin-1-yl group, 4-dimethylaminopiperidin-1-yl group,4-hydroxypiperidin-1-yl group, morpholin-4-yl group,

2-aminomethylmorpholin-4-yl group,

2-methylaminomorpholin-4-yl group,

2-dimethylaminomorpholin-4-yl group, thiomorpholin-4-yl group,homopiperazin-1-yl group, 4-methylhomopiperazin-1-yl group,N-thiazolidinyl group, and N-oxazolidinyl group.

The optionally protected amino group represented by R⁶ include aminogroup as well as amino group protected by an appropriate protectivegroup. Exemplary such protected amino groups include the amino groupprotected with a lower alkanoyl group such as formyl, acetyl, propionyl,pivaloyl, hexaloyl, or the like; a lower alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl,t-pentyloxycarbonyl, hexyloxycarbonyl, or the like; an aroyl such asbenzoyl, toluoyl, naphthoyl, or the like; an aryl lower alkanoyl groupsuch as phenylacetyl, phenylpropionyl, or the like; an aryloxycarbonylgroup such as phenoxycarbonyl, naphthyloxycarbonyl, or the like; anaryloxy lower alkanoyl group such as phenoxyacetyl, phenoxypropionyl, orthe like; an aralkyloxycarbonyl group such as benzyloxycarbonyl,phenethyloxycarbonyl, or the like; or an aralkyl group such as benzyl,phenethyl, benzhydryl, trityl, or the like.

The preferable combination of the R¹, R², R³, R⁴, R⁵, R⁶, X, Y, Z, and Wis such that R¹ is hydrogen atom, R² is amino group, a lower alkylaminogroup, or a di-lower alkylamino group, R³ is a halogen atom, R⁴ is ahalogen atom, X is nitrogen atom, Y and Z are --CH═ or --CR⁷ ═ (whereinR⁷ is a lower alkyl group or a halogen atom), W is --CR⁸ ═ (R⁸ is ahalogen atom or a lower alkyl group), R⁵ is a group represented byformula (a) (e=3 or 4), and R⁶ is hydrogen atom. The more preferablecombination of the R¹, R², R³, R⁴, R⁵, R⁶, X, Y, Z, and W is such thatR¹ is hydrogen atom, R² is amino group, R³ is fluorine atom, R⁴ isfluorine atom, X is nitrogen atom, Y is --CF═, Z is --CH═, W is --CCl═,--CBr═ or --CCH₃ ═, R⁵ is a group represented by formula (a) (e=3), andR⁶ is hydrogen atom.

The salts of the pyridonecarboxylic acid derivatives of the formula (1)as described above may be either acid adduct salts or base adduct salts.The term, salts used herein also include chelate salts with a boroncompound. Exemplary acid adduct salts include (i) salts with a mineralacid such as hydrochloric acid or sulfuric acid; (ii) salts with anorganic carboxylic acid such as formic acid, citric acid,trichloroacetic acid, trifluoroacetic acid, fumaric acid, or maleicacid; and (iii) salts with a sulfonic acid such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid,or naphthalenesulfonic acid; and exemplary base adduct salts include(i') salts with an alkaline metal such as sodium or potassium; (ii')salts with an alkaline earth metal such as calcium or magnesium; (iii')ammonium salts; (iv') salts with a nitrogen-containing organic base suchas trimethylamine, triethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,diethylamine, cyclohexylamine, procaine, dibenzylamine,N-benzyl-β-phenethylamine, 1-ephenamine, orN,N'-dibenzylethylenediamine. Exemplary boron compounds include boronhalides such as boron fluoride, and lower acyloxyborons such asacetoxyboron.

The pyridonecarboxylic acid derivatives and the salts thereof of thepresent invention may also be in the form of a hydrate or a solvate inaddition to the non-solvated form. Accordingly, the compound of thepresent invention includes all of the crystalline form, the hydrateform, and the solvate form. Furthermore, the pyridonecarboxylic acidderivatives and the salts thereof may be present in the form of anoptically active substance, and such optically active substance is alsowithin the scope of the compounds of the present invention. Stillfurther, the pyridonecarboxylic acid derivative and the salt thereof maybe present in the form of a (cis or trans) stereoisomer, and suchstereoisomer is also within the scope of the compounds of the presentinvention.

The pyridonecarboxylic acid derivatives and the salts thereof of thepresent invention represented by the formula (1) as described above maybe produced by any procedure appropriately selected in accordance withsuch factors as the type of the substituents, and an exemplary procedureis as described below.

(Procedure 1)

Of the compounds represented by the general formula (1), the compounds(1a) wherein R¹ is hydrogen atom or a lower alkyl group, and R⁵ is ahalogen atom may be produced, for example, by Procedure 1 represented bythe reaction scheme as described below: ##STR4## [wherein R^(1a)represents a lower alkyl group; R¹⁰ represents a lower alkyl group; L¹represents a halogen atom; R^(5a) represents a halogen atom; R^(2a)represents hydroxyl group, a lower alkoxy group, or a substituted orunsubstituted amino group or protected amino group; R^(6a) representshydrogen atom, a halogen atom, or nitro group; R^(6b) represents anoptionally substituted amino group; R², R³, R⁴, R⁶, X, Y, Z, and W areas defined above.]

More illustratively, the compound (1a) of the present invention isproduced by reacting compound (A) with an orthoformate such as methylorthoformate or ethyl orthoformate to produce acrylate derivative (B);reacting the acrylate derivative (B) with an amino compound (C) toproduce compound (D); cyclizing the compound (D) to produce compound(E); and hydrolyzing the compound (E) to obtain the compound (1a).

The reaction between the compound (A) and the orthoformate is generallycarried out at 0 to 160° C., and preferably 50 to 150° C. usually for areaction period of 10 minutes to 48 hours, and preferably for 1 to 10hours. The orthoformate is used in equimolar amount or more to thecompound (A), and preferably, in 1 to 10 times the molar amount to thecompound (A).

The reaction with the compound (C) may be effected with no solvent or ina solvent. The solvent used in this reaction may be any solvent as longas the reaction is not affected by the solvent, and the exemplarysolvents include aromatic hydrocarbons such as benzene, toluene, andxylene; ethers such as diethylether, tetrahydrofuran, dioxane,monoglyme, and diglyme; aliphatic hydrocarbons such as pentane, hexane,heptane, and ligroin; halogenated hydrocarbons such as methylenechloride, chloroform, and carbon tetrachloride; nonprotonic polarsolvents such as dimethylformamide and dimethylsulfoxide; and alcoholssuch as methanol, ethanol and propanol. This reaction is generallyconducted at 0 to 150° C., and preferably at 0 to 100° C. usually for areaction period of 10 minutes to 48 hours. The compound (C) is used inequimolar amount or more to the compound (A), and preferably, in 1 to 2times the molar amount to the compound (A).

Alternatively, compound (A) may be reacted with an acetal such asN,N-dimethylformamide dimethylacetal or N-dimethylformamidediethylacetal, and then, with compound (C) to produce the compound (D).The solvent used in the reaction with the acetal may be any solvent aslong as the reaction is not affected by the solvent, and the exemplarysolvents are those described in the foregoing. This reaction isgenerally conducted at 0 to 150° C., and preferably at room temperatureto 100° C. generally for a reaction period of 10 minutes to 48 hours,and preferably for 1 to 10 hours.

Next, the cyclization of the compound (D) into the compound (E) isconducted in an adequate solvent either in the presence or absence of abasic compound. The solvent used in this reaction may be any solvent aslong as the reaction is not affected by the solvent, and the exemplarysolvents include aromatic hydrocarbons such as benzene, toluene, andxylene; ethers such as diethylether, tetrahydrofuran, dioxane, andmonoglyme; halogenated hydrocarbons such as methylene chloride,chloroform, and carbon tetrachloride; alcohols such as methanol,ethanol, propanol, and butanol; and nonprotonic polar solvents such asdimethylformamide and dimethylsulfoxide. Exemplary basic compounds usedare alkaline metals such as metal sodium and metal potassium; metalhydrides such as sodium hydride and calcium hydride; inorganic saltssuch as sodium hydroxide, potassium hydroxide, sodium carbonate, andpotassium carbonate; alkoxides such as sodium methoxide, sodiumethoxide, and potassium t-butoxide; metal fluorides such as sodiumfluoride and potassium fluoride; organic salts such as triethylamine and1,8-diazabicyclo[5.4.0]undecene (DBU). This reaction is conducted at areaction temperature of 0 to 200° C., and preferably, at roomtemperature to 180° C., and the reaction is generally completed in 5minutes to 24 hours. The basic compound is used in equimolar amount ormore to the compound (D), and preferably, in 1 to 2 times the molaramount to the compound (D).

The compound (E) is subjected to hydrolysis to eliminate the carboxylprotective group R^(1a) and/or the amino protective group R^(2a) toobtain compound (1a).

The hydrolysis may be conducted under any conditions commonly used inthe hydrolysis, for example, in the presence of a basic compound such assodium hydroxide, potassium hydroxide, sodium carbonate, and potassiumcarbonate, a mineral acid such as hydrochloric acid, sulfuric acid, andhydrobromic acid, or an organic acid such as p-toluenesulfonic acid, andin a solvent such as water, an alcohol such as methanol, ethanol orpropanol, or an ether such as tetrahydrofuran or dioxane, a ketone suchas acetone or methylethylketone, acetic acid, or a mixture of suchsolvents. The reaction is generally conducted at room temperature to180° C., and preferably, at room temperature to 140° C. usually for areaction period of 1 to 24 hours.

It should be noted that in the case of producing a compound wherein R⁶in formula (1) is an optionally protected amino group, the compound (E)is first produced through the reactions as described above by using acompound (A) wherein R^(6a) is a halogen atom or nitro group for thestarting material, and the compound (E^(1a)) is then produced byaminating said halogen atom or by reducing the nitro group, and thecompound (1a) is derived from the compound (E^(1a)) by eliminating theamino protective group if necessary and eliminating the carboxylprotective group.

(Procedure 2)

Of the compounds represented by the general formula (1), the compoundswherein R⁵ is an optionally substituted saturated cyclic amino group maybe produced, for example, by the procedure 2 represented by the reactionscheme as described below: ##STR5## [wherein R^(5b) represents anoptionally substituted saturated cyclic amino group; and R¹, R², R³, R⁴,R^(5a), R⁶ , X, Y, Z, and W are as defined above.]

More illustratively, compound (G) is obtained by aminating compound (F)using the compound represented by the formula: R^(5b) --H.

This reaction may be conducted in a solvent which does not affect thereaction such as an aromatic hydrocarbon such as benzene, toluene, orxylene; an alcohol such as methanol or ethanol; an ether such astetrahydrofuran, dioxane, or monoglyme; a halogenated hydrocarbon suchas methylene chloride, chloroform, or carbon tetrachloride; anonprotonic polar solvent such as dimethylformamide, dimethylsulfoxide,or N-methylpyrrolidone; acetonitrile, or pyridine, and in the optionalpresence of a neutralizer such as sodium carbonate, calcium carbonate,sodium hydrogencarbonate, triethylamine, 1,8-diazabicyclo[5.4.0]undecene(DBU) at room temperature to 160° C. The reaction period is from severalminutes to 48 hours, and preferably, from 10 minutes to 24 hours. Thecompound R^(5b) --H is used in equimolar amount or more to the compound(F), and preferably, in 1 to 5 times the molar amount to the compound(F). It should be noted that the compound (F) may be obtained as in theProcedure 1 as described above, and that, when R¹ is a carboxylprotective group, it may be replaced with a hydrogen atom by hydrolysis.

(Procedure 3)

Of the compounds represented by the general formula (1), the compoundswherein R¹ is a carboxyl protective group may be produced, for example,by the procedure 3 represented by the reaction scheme as describedbelow: ##STR6## [wherein R^(1b) represents a carboxyl protective group;L² represents a halogen atom; and R², R³, R⁴, R⁵, R⁶, X, Y, Z, and W areas defined above.]

More illustratively, compound (I) is obtained by reacting compound (H)with a halogen compound: R^(1b) --L². The solvents which may be used inthis reaction include aromatic hydrocarbons such as benzene and toluene;halogenated hydrocarbons such as methylene chloride and chloroform;nonprotonic polar solvents such as dimethylformamide anddimethylsulfoxide; and inert solvents such as acetonitrile. The reactiontemperature is usually from room temperature to 100° C. The reaction ispreferably conducted in the presence of a basic compound such astriethylamine, diisopropylethylamine, dicyclohexylamine, DBU, sodiumcarbonate, potassium carbonate, and sodium hydroxide. It should be notedthat the compound (H) may be obtained by the Procedure 1 and Procedure 2as described above.

When amino group, imino group, hydroxy group, mercapto group, carboxylgroup or the like which is not involved in the reaction is present inthe starting materials of the Procedure 1, 2, or 3 as described above,such group may be protected during the reaction, and the protectivegroup may be eliminated after the completion of the reaction by aconventional method. The protective group used in such a case may be anygroup as long as the compound of the present invention produced by thereaction can be deprotected with no decomposition of its structure, andany group commonly used in the field of peptide, amino sugar, andnucleic acid chemistry may be preferably used ("Protective Groups inOrganic Synthesis", Second Editor, T. W. Green and P. G. M. Wuts, JohnWiley & Sons Inc., 1991).

1) J. Heterocyclic Chem. 22, 1033 (1985)

2) Liebigs Ann. Chem. 29 (1987)

3) J. Med. Chem. 31, 991 (1988)

4) J. Org. Chem. 35, 930 (1970)

5) Japanese Patent Application Laid-Open No. 62-246541

6) Japanese Patent Application Laid-Open No. 62-26272

7) Japanese Patent Application Laid-Open No. 63-145268

8) J. Med. Chem. 29, 2363 (1986)

9) J. Fluorin Chem. 28, 361 (1985)

10) Japanese Patent Application Laid-Open No. 63-198664

11) Japanese Patent Application Laid-Open No. 63-264461

12) Japanese Patent Application Laid-Open No. 63-104974

13) European Patent Application No. 230948

14) Japanese Patent Application Laid-Open No. 2-282384

15) Published Japanese Translation of PCT International Publication forPatent Application No. 3-502452

16) J. Het. Chem. 27, 1609 (1990)

The starting compound (C) may be produced by any process, and anexemplary production process is as described below.

The starting compound (C) may be obtained by replacing the halogen atombonded to the carbon atom constituting the 6-membered ring with an aminesuch as ammonia, an alkylamine, benzylamine, or the like by a knownhalogen-amine substitution reaction. It should be noted that when asubstituted amine such as an alkyl amine or benzyl amine is used for theamine, the substituent of the substituted amino group may be adequatelyeliminated by a conventional method as shown in the reaction scheme,below. When R^(2a) is a substituted or unsubstituted amino group oramino group substituted with a protective group, similar halogen-aminereplacement reaction may be conducted. ##STR7## [In the formula, Halrepresents a halogen atom such as F or Cl; Hc.NH and Hc'.NH arerespectively a substituted amino group or an amino group substitutedwith a protective group; Hc.NH₂ and Hc'.NH₂ are respectively an aminethereof. R^(2b) represents hydroxyl group or a lower alkoxy group. R³,X, Y, and Z are as defined above.]

When there is no readily available candidate starting material, namely,the di-halogen-substituted nitrogen-containing six-membered ringcompound having the substituents corresponding to the substituents (R³,and when X, Y and Z are --CR⁷ ═ or --CH═ , R⁷ or hydrogen) on thenitrogen-containing six-membered ring of the target substance, thetarget substance can be produced by using a more readily availabledi-halogen-substituted nitrogen-containing six-membered ring compoundfor the starting material. More illustratively, an adequate substituentreplacement reaction may be effected simultaneously with thehalogen-amine replacement reaction by the substituted amino group.Exemplary useful substituent replacement reactions are the processwherein the halogen atom is replaced with amino group, and the aminogroup is further replaced with another halogen atom or cyano group bysuch reaction as Sandmeyer reaction of Schiemann reaction; the processwherein the halogen atom is replaced with hydroxyl group, and thehydroxyl group is further replaced with another halogen atom by using aphosphorus halide or a phosphorus oxyhalide; the process wherein thebromine atom or the chlorine atom is replaced with fluorine atom byusing such reagent as potassium fluoride; the process wherein thehalogen atom is replaced with hydrogen atom by hydrogenation; theprocess wherein the alkoxycarbonyl group or the acyl group is reducedinto a lower alkyl group by using a hydride compound; the processwherein the carboxyl group is replaced with hydrogen atom bydecarboxylation; and combination of the above-mentioned processes. Itshould be noted that, when the compound having the thus introduced aminogroup or hydroxyl group is subjected to a further substituentreplacement reaction, protection of the amino group or the hydroxylgroup is sometimes necessary. In such a case, the protection may beaccomplished by phthalimidation in the case of the amino group, and bybenzyloxidation in the case of the hydroxyl group. The protected groupmay be deprotected in the subsequent adequate stage. The halogen atominvolved in the halogen-amine replacement reaction which is representedby Hal in the reaction scheme as shown above is not limited to anyparticular type. The halogen atom, however, is preferably fluorine atomwith high reactivity. In such a case, if fluorine atom is present as asubstituent in any of the highly reactive other sites, such site may beprotected by replacing the fluorine atom with another halogen atom suchas bromine atom or chlorine atom by the reactions as described above.

Alternatively, the starting compound (c) can be produced by reducing thenitro group into amino group by a normal process as shown in thefollowing reaction scheme. ##STR8## [In the formula, R^(2b), R³, X, Yand Z are as defined above.]

The thus obtained compound of the present invention is isolated andpurified in accordance with a standard method. The compound is obtainedin the form of a salt, a free carboxylic acid, or a free amine dependingon the conditions of the isolation and the separation. The form of thecompound, however, may be converted mutually, the compounds of thepresent invention can be prepared in desired form.

The compound represented by the general formula (1), above or the saltthereof may be formulated into an antibacterial composition with apharmaceutically acceptable carrier adapted for parenteraladministration such as injection, transrectal administration, or eyedrop, or oral administration in solid or liquid form.

When the antibacterial composition of the present invention is in theform of an injection, it may be in the form of a solution, a suspensionor an emulsion in a pharmaceutically acceptable sterilized water or anon-aqueous medium. Examples of appropriate non-aqueous carriers,diluents, media, and vehicles include propylene glycol, polyethyleneglycol, vegetable oils such as olive oil, and organic esters adequatefor injection such as ethyl oleate. Such composition may also containadditives such as a preservative, a wetting agent, an emulsifier and adispersant. The composition may be sterilized, for example, byfiltration through a bacteria-removing filter, or by incorporating asterilizer in the form of a sterilizer or a sterile solid compositionsoluble in a sterilizable medium for injection just before its use.

A preparation for eye drop administration may preferably contain asolubilizer, a preservative, an isotonizing agent, a thickening agent,and the like in addition to the compound of the present invention.

Solid preparations for oral administration include capsules, tablets,pills, powders, and granules. In preparing such solid preparations, thecompounds of the present invention are typically mixed with at least oneinert diluent such as sucrose, lactose or starch. The preparation mayalso contain substances other than the inert diluents such as lubricant(for example, magnesium stearate etc.). In the case of capsules, tabletsor pills, the preparation may also include a buffer. The tablets and thepills may have an enteric coating.

Liquid preparations for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining an inert diluent normally used in the art such as water. Inaddition to such inert diluent, the composition may also containadditives such as a wetting agent, an emulsifying agent, a suspendingagent as well as a sweetener, a seasoning, and a flavor.

Preparations for enteral administrations may preferably contain anexcipient such as cacao butter or suppository wax in addition to thecompound of the present invention.

The dosage of the compound of the present invention varies depending onthe nature of the compound administered, route of administration, thedesired treatment period, and other factors. The compounds of thepresent invention, however, are typically administered at about 0.1 to1000 mg/kg per day, and in particular, at about 0.5 to 100 mg/kg perday. If desired, such dose may be administered in 2 to 4 portions.

The novel pyridonecarboxylic acid derivatives and salts of the presentinvention exhibit very strong antibacterial actions as well as lowphototoxicity and cytotoxicity, and therefore, would be widelyapplicable as pharmaceuticals for human and other animals as well aspharmaceuticals for fishes, pesticides, food preservatives, and thelike. The compound of the present invention is also expected to exhibitantivirus properties, and especially, anti-HIV (human immunodeficiencyvirus) actions, and to be effective in preventing and treating AIDS.

Next, the present invention is described in further detail by referringto Examples and Reference Examples, which by no means limit the scope ofthe present invention.

REFERENCE EXAMPLE 1

Synthesis of 2-(t-butylamino)-3,5,6-trifluoropyridine

To 40 ml of acetonitrile were added 11.0 g of2,3,5,6-tetrafluoropyridine and 18.5 g of t-butylamine, and the mixturewas stirred at 60° C. for 3 days, and the solvent and the like weredistilled off. To the residue was added 100 ml of chloroform, and themixture was washed with 50 ml of distilled water. The chloroform layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure to obtain 9.7 g of the title compound as a pale yellowoil.

¹ HNMR (CDCl₃) δ;

1.45 (s, 9H), 4.40 (brs, 1H), 7.16 (ddd, J=7 Hz, 8 Hz, 9 Hz, 1H)

REFERENCE EXAMPLE 2

Synthesis of 2-benzylamino-6-(t-butylamino)-3,5-difluoropyridine

To 20 ml of N-methylpyrrolidone were added 9.7 g of2-(t-butylamino)-3,5,6-trifluoropyridine together with 15.5 g ofbenzylamine, and the mixture was stirred at 160° C. for one day andallowed to cool. After adding 50 ml of chloroform, the mixture waswashed three times with 500 ml of distilled water. The chloroform layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure to obtain about 16.5 g of the title compound as a darkgreen oil.

REFERENCE EXAMPLE 3

Synthesis of 2-amino-6-(t-butylamino)-3,5-difluoropyridine

To 60 ml of methanol were added 10.7 g of the crude2-benzylamino-6-(t-butylamino)-3,5-difluoropyridine as described abovetogether with 1.10 g of 10% palladium carbon and 3.8 g of concentratedhydrochloric acid, and the mixture was hydrogenated for one day. Thecatalyst was separated by filtration, and the solvent and the like weredistilled off under reduced pressure. To the residue was added 150 ml ofchloroform, and the mixture was washed with 80 ml of 10% aqueoussolution of sodium carbonate, and the washings were extracted again with50 ml of chloroform. The chloroform layers were combined, and dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was subjected to chromatography (silica gel, 100 g;eluent:chloroform:n-hexane, 2:1, and then, chloroform) to obtain 3.3 gof the title compound as a pale brown oil.

¹ HNMR (CDCl₃) δ;

1.43 (s, 9H), 4.11 (brs, 2H), 6.94 (t, J=10 Hz, 1H)

EXAMPLE 1

Synthesis of ethyl1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 15 ml of chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 4.20g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 3.30 g of 2-amino-6-(t-butylamino)-3,5-difluoropyridine. Thesolution was concentrated under reduced pressure to obtainorange-colored solid residue. To this residue were added 4.0 g ofanhydrous potassium carbonate and 8 ml of N,N-dimethylformamide, and themixture was stirred at 90° C. for 10 minutes and allowed to cool. Thesolution was separated by adding 50 ml of chloroform and 500 ml ofdistilled water, and the chloroform layer was washed twice with 500 mlof distilled water, dried over anhydrous magnesium sulfate, concentratedunder reduced pressure, and allowed to stand. The precipitate wascollected by filtration, washed with ethanol and diisopropylethersuccessively to obtain 4.67 g of the title compound as a colorlesspowder.

Melting point: 203 to 205° C.

¹ HNMR (CDCl₃) δ;

1.39 (s, 9H), 1.40 (t, J=7 Hz, 3H), 4.40 (q, J=7 Hz, 2H), 4.70 (brs,1H), 7.21 (dd, J=8 Hz, 10 Hz, 1H), 8.31 (dd, J=8 Hz, 10H, 1H), 8.50 (s,1H)

EXAMPLE 2

Synthesis of ethyl8-bromo-1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 5 ml of chloroform solution of ethyl3-ethoxy-2-(3-bromo-2,4,5-trifluorobenzoyl)acrylate prepared from 1.32 gof ethyl 3-bromo-2,4,5-trifluorobenzoylacetate by normal process wasadded 2-amino-6-(t-butylamino)-3,5-difluoropyridine until completion ofthe conversion into the aminoacrylate form was confirmed by monitoringthe reaction by TLC. The solution was concentrated under reducedpressure to obtain yellow solid residue. To this residue were added 1.2g of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide,and the mixture was stirred at 90° C. for 15 minutes and allowed tocool. The solution was separated by adding 30 ml of chloroform and 300ml of distilled water, and the chloroform layer was washed twice with300 ml of distilled water, dried over anhydrous magnesium sulfate,concentrated under reduced pressure, and allowed to stand. Theprecipitate was collected by filtration, washed with ethanol anddiisopropylether successively to obtain 1.41 g of the title compound asa colorless powder.

Melting point: 198 to 203° C.

¹ HNMR (CDCl₃) δ;

1.38 (s, 9H), 1.40 (t, J=7 Hz, 3H), 4.40 (q, J=7 Hz, 2H), 4.71 (brs,1H), 7.20 (dd, J=8 Hz, 10 Hz, 1H), 8.36 (dd, J=9 Hz, 10H, 1H), 8.54 (s,1H)

EXAMPLE 3

Synthesis of ethyl1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 1 ml chloroform solution of ethyl3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylate prepared from 0.27 g ofethyl 2,3,4,5-tetrafluorobenzoylacetate by normal process was added2-amino-6-(t-butylamino)-3,5-difluoropyridine until completion of theconversion into the aminoacrylate form was confirmed by monitoring thereaction by TLC. The solution was concentrated under reduced pressure.To the residue were added 0.6 g of anhydrous potassium carbonate and 1ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for15 minutes and allowed to cool. The solution was separated by adding 30ml of chloroform and 300 ml of distilled water, and the chloroform layerwas washed twice with 300 ml of distilled water, dried over anhydrousmagnesium sulfate, concentrated under reduced pressure, and allowed tostand. The precipitate was collected by filtration, washed with ethanoland diisopropylether successively to obtain 0.15 g of the title compoundas a colorless powder.

Melting point: 174 to 178° C.

¹ HNMR (CDCl₃) δ;

1.40 (t, J=7 Hz, 3H), 1.42 (s, 9H), 4.40 (q, J=7 Hz, 2H), 4.71 (brs,1H), 7.25 (dd, J=8 Hz, 10 Hz, 1H), 8.16 (ddd, J=2 Hz, 8 Hz, (10H, 1H),8.48 (s, 1H)

EXAMPLE 4

Synthesis of ethyl1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3-carboxylate

To 1 ml chloroform solution of ethyl3-ethoxy-2-(2,6-dichloro-5-fluoronicotinoyl)acrylate prepared from 0.27g of ethyl 2,6-dichloro-5-fluoronicotinoylacetate by normal process wasadded 2-amino-6-(t-butyl)amino-3,5-difluoropyridine until completion ofthe conversion into the aminoacrylate form was confirmed by monitoringthe reaction by TLC. The solution was concentrated under reducedpressure. To the residue were added 0.5 g of anhydrous potassiumcarbonate and 1 ml of N,N-dimethylformamide, and the mixture was stirredat 90° C. for 15 minutes and allowed to cool. The solution was separatedby adding 30 ml of chloroform and 300 ml of distilled water, and thechloroform layer was washed twice with 300 ml of distilled water, driedover anhydrous magnesium sulfate, concentrated under reduced pressure,and allowed to stand. The precipitate was collected by filtration,washed with ethanol and diisopropylether successively to obtain 0.19 gof the title compound as yellow crystals.

Melting point: 158 to 160° C.

¹ HNMR (CDCl₃) δ;

1.39 (t, J=7 Hz, 3H), 1.45 (s, 9H), 4.40 (q, J=7 Hz, 2H), 4.68 (brs,1H), 7.27 (t, J=9 Hz, 1H), 8.48 (d, J=7 Hz 1H), 8.75 (s, 1H)

EXAMPLE 5

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a mixed solution of 10 ml of 4N hydrochloric acid and 10 ml of aceticacid was added 4.10 g of ethyl1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was stirred under reflux condition for 5 hours. Afteradding 20 ml of distilled water, the solution was allowed to cool. Theprecipitate was collected by filtration, and washed with ethanol anddiisopropylether successively to obtain 3.32 g of the title compound asa colorless powder.

Melting point: 280° C. or higher

¹ HNMR (d₆ -DMSO) δ;

6.80 (s, 2H), 7.99 (t, J=9 Hz, 1H), 8.38 (t, J=9 Hz, 1H), 8.93 (s, 1H)

REFERENCE EXAMPLE 4

Synthesis of 2-benzylamino-3,5,6-trifluoropyridine

To 50 ml of acetonitrile were added 12.0 g of2,3,5,6-tetrafluoropyridine and 18.0 g of benzylamine, and the mixturewas stirred under reflux condition for 2 hours, and the solvent and thelike were distilled off. To the residue was added 150 ml of ethylacetate, and the mixture was washed twice with 150 ml of distilled waterand 150 ml of 10% aqueous solution of citric acid. The ethyl acetatelayer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure to obtain 16.0 g of the title compound as a pale yellowoil.

¹ HNMR (CDCl₃) δ;

4.58 (d, J=6 Hz, 2H), 4.81 (brs, 1H), 7.23 (m, 1H), 7.35 (m, 5H)

REFERENCE EXAMPLE 5

Synthesis of 2-amino-3,5,6-trifluoropyridine

To 40 ml of methanol were added 7.60 g of the crude2-benzylamino-3,5,6-trifluoropyridine as described above together with0.55 g of 10% palladium on carbon and 2 ml acetic acid, and the mixturewas hydrogenated at 50° C. for one day. The catalyst was separated byfiltration, and the solvent and the like were distilled off underreduced pressure. The precipitate was dispersed in n-hexane, andcollected by filtration to obtain 3.85 g of the title compound as acolorless solid.

¹ HNMR (CDCl₃) δ;

4.53 (brs, 2H), 7.27 (m, 1H)

REFERENCE EXAMPLE 6

Synthesis of 2-amino-3,5-difluoro-6-(p-methoxybenzylamino)-pyridine

To 10 ml of N-methylpyrrolidone were added 3.90 g of2-amino-3,5,6-trifluoropyridine and 7.60 g of p-methoxybenzylamine, andthe mixture was stirred under nitrogen atmosphere at 140° C. for one dayand allowed to cool. To the solution was added 50 ml of chloroform, andthe solution was washed three times with 500 ml of distilled water. Thechloroform layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure, and the residue was subjected tochromatography (silica gel, 32 g; eluent: chloroform) to obtain 4.50 gof the title compound as a pale yellow crude oil.

¹ HNMR (CDCl₃) δ;

3.80 (s, 3H), 4.18 (brs, 1H), 4.49 (brs, 3H), 6.87 (d, J=9 Hz, 2H), 6.99(t, J=10 Hz, 1H), 7.28 (t, J=10 Hz, 2H)

EXAMPLE 6

Synthesis of ethyl8-chloro-1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 18 ml of chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 2.52g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 2.65 g of 2-amino-3,5-difluoro-6-(p-methoxybenzylamino)pyridine.The solution was concentrated under reduced pressure, and to the residuewere added 2.5 g of anhydrous potassium carbonate and 6 ml ofN,N-dimethylformamide, and the mixture was stirred at 90° C. for 15minutes and allowed to cool. The solution was separated by adding 50 mlof chloroform and 500 ml of distilled water, and the chloroform layerwas washed twice with 500 ml of distilled water, dried over anhydrousmagnesium sulfate, concentrated under reduced pressure, and allowed tostand. The precipitate was dispersed in ethanol, collected byfiltration, and washed with ethanol to obtain 3.20 g of the titlecompound as a yellow powder.

Melting point: 197 to 200° C.

¹ HNMR (CDCl₃) δ;

1.40 (t, J=7 Hz, 3H), 3.80 (s, 3H), 4.41 (q, J=7 Hz, 2H), 4.48 (m, 2H),5.10 (brs, 1H), 6.83 (d, J=7 Hz, 2H), 7.20 (d, J=7 Hz, 2H), 7.25 (dd,J=8 Hz, 9 Hz, 1H), 8.31 (dd, J=8 Hz, 10 Hz, 1H), 8.47 (s, 1H)

EXAMPLE 7

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a mixed solution of 6 ml of 4N hydrochloric acid and 6 ml of aceticacid was added 3.00 g of ethyl8-chloro-1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux with stirring for 16 hours. Thesolution was allowed to cool and stand, and the precipitate wascollected by decantation, and washed by adding a small amount ofdistilled water, shaking, allowing to stand, and decanting. To theprecipitate was added 10 ml of ethanol, and the mixture was heated underreflux with stirring for 1 hour and allowed to cool and stand, and theprecipitate was collected by decantation. To this precipitate was againadded 10 ml of chloroform, and the mixture was stirred under refluxcondition for 1 hour and allowed to cool, and the precipitate wascollected by filtration and washed with ethanol and diisopropylethersuccessively to obtain 1.25 g of the title compound as a pale brownpowder.

EXAMPLE 8

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-7-[(3S)-3-aminopyrrolidin-1-yl]-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 250 mg of N,N-dimethylformamide were added 60 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid and 60 mg of (3S)-3-aminopyrrolidine, and the mixture was heatedunder reflux with stirring at 90° C. for 1 hour. After adding 1 ml ofethanol, the mixture was allowed to cool, and the precipitate wascollected by filtration and washed with ethanol and diisopropylethersuccessively to obtain 41 mg of the title compound as a pale brownpowder.

Melting point: 248 to 250° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

1.73 (m, 1H), 2.03 (m, 1), 4.67 (m, 2H), 6.75 (brs, 2H), 7.95 (t, J=9Hz, 1H), 7.98 (d, J=14 Hz, 1H), 8.73 (s, 1H)

(Part of signals overlapped with the proton of water, and wereundistinguishable.)

EXAMPLE 9

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 350 mg of N,N-dimethylformamide were added 100 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 80 mg of 3-aminoazetidine dihydrochloride and 150 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour.After adding 1 ml of ethanol, the mixture was allowed to cool, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 86 mg of the title compound as acolorless powder.

Melting point: 260 to 263° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.73 (m, 1H), 4.09 (m, 2H), 4.67 (m, 2H), 6.74 (brs, 2H), 7.86 (d, J=14Hz, 1H), 7.94 (t, J=9 Hz, 1H), 8.68 (s, 1H)

EXAMPLE 10

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-methylaminoazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 400 mg of N,N-dimethylformamide were added 90 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 80 mg of 3-methylaminoazetidine dihydrochloride, and 160 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour.After adding 0.5 ml of ethanol, the mixture was allowed to cool, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 92 mg of the title compound as acolorless powder.

Melting point: 259 to 265° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

2.20 (s, 3H), 3.48 (m, 1H), 4.14 (m, 2H), 4.64 (m, 2H), 6.75 (brs, 2H),7.86 (d, J=14 Hz, 1H), 7.94 (t, J=9 Hz, 1H), 8.68 (s, 1H)

EXAMPLE 11

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-7-(3-amino-3-methylazetidin-1-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 350 mg of N,N-dimethylformamide were added 80 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 60 mg of 3-amino-3-methylazetidine dihydrochloride, and 150 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 40minutes. After adding 0.5 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol to obtain 64 mg of the title compound as a pale yellow powder.

Melting point: 280° C. or higher

¹ HNMR (d₆ -DMSO) δ;

1.35(s, 3H), 4.19 (m, 2H), 4.30 (m, 2H), 6.75 (brs, 2H), 7.86 (d, J=14Hz, 1H), 7.94 (t, J=9 Hz, 1H), 8.68 (s, 1H)

EXAMPLE 12

Synthesis of 3-hydroxyazetidine salt of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid p To 800 mg of acetonitrile were added 100 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 60 mg of 3-hydroxyazetidine hydrochloride, and 150 mg ofN-methylpyrrolidine, and the mixture was heated under reflux for 1 hour.The precipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 56 mg of the title compound as acolorless powder.

Melting point: 185 to 190° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.45 (m, 2H), 3.65 (m, 2H), 4.14 (m, 2H), 4.39 (m, 1H), 4.46 (m, 1H),4.68 (m, 2H), 6.70 (brs, 2H), 7.80 (d, J=14 Hz, 1H), 7.91 (t, J=9 Hz,1H), 8.52 (s, 1H)

EXAMPLE 13

Synthesis of N-methylpyrrolidine salt of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 2000 mg of N,N-dimethylformamide were added 300 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 110 mg of 3-hydroxyazetidine hydrochloride, and 300 mg ofN-methylpyrrolidine, and the mixture was stirred at 80° C. for 10 hours.After adding 2 ml of ethanol, the mixture was allowed to cool, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 222 mg of the title compound asa colorless powder.

Melting point: 234 to 238° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

1.67 (m, 4H), 2.24 (s, 1H), 2.38 (m, 4H), 4.18 (m, 2H), 4.47 (m, 1H),4.71 (m, 2H), 5.73 (m, 1H), 6.75 (brs, 2H), 7.86 (d, J=14 Hz, 1H), 7.94(t, J=9 Hz, 1H), 8.67 (s, 1H)

EXAMPLE 14

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-7-piperazino-1,4-dihydroquinoline-3-carboxylicacid

To 170 mg of N,N-dimethylformamide were added 50 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 50 mg of piperazine, and the mixture was stirred at 90° C. for 1hour. After adding about 0.3 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 33 mg of the titlecompound as a colorless powder.

Melting point: 273 to 277° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

2.82 (m, 4H), 3.16 (m, 4H), 6.76 (brs, 2H), 7.95 (t, J=9 Hz, 1H), 8.05(d, J=12 Hz, 1H), 8.79 (s, 1H)

REFERENCE EXAMPLE 7

Synthesis of 3,5,6-trifluoro-2-(methylamino)pyridine

To 10 ml of acetonitrile were added 4.5 g of 2,3,5,6-tetrafluoropyridineand 10 ml of methylamine (10% aqueous solution), and the mixture wasstirred at 50° C. for 2 hours. To the solution was added 50 ml ofchloroform, and the mixture was washed four times with 250 ml ofdistilled water. The chloroform layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to obtain the titlecompound as a pale brown crude oil.

¹ HNMR (CDCl₃) δ;

2.99 (d, J=5 Hz, 3H), 4.53 (brs, 1H), 7.20 (ddd, J=7 Hz, 8 Hz, 9 Hz, 1H)

REFERENCE EXAMPLE 8

Synthesis of 2-benzylamino-3,5-difluoro-6-(methylamino) pyridine

To 20 ml of N-methylpyrrolidone were added all amount of theabove-described 3,5,6-trifluoro-2-(methylamino)-pyridine together with10 g of benzylamine, and the mixture was stirred at 140° C. for 19 hoursand allowed to cool. To the solution was added 50 ml of chloroform andthe mixture was washed six times with 200 ml of distilled water. Thechloroform layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain the title compound as acrude oil.

REFERENCE EXAMPLE 9

Synthesis of 2-amino-3,5-difluoro-6-(methylamino)pyridine

To a mixed solution of 10 ml of methanol and 1 ml of concentratedhydrochloric acid were added all amount of the above described2-benzylamino-3,5-difluoro-6-(methylamino)pyridine together with 0.55 gof 10% palladium on carbon, and the mixture was hydrogenated at 50° C.overnight. The catalyst was separated by filtration, and the solvent andthe like were distilled off under reduced pressure. To the residue wasadded 50 ml of chloroform, and the mixture was washed with 50 ml of 5%aqueous solution of sodium carbonate. The chloroform layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The solid precipitate was collected by filtration to obtain840 mg of the title compound as a pale gray solid.

¹ HNMR (CDCl₃) δ;

2.95 (d, J=5 Hz, 3H), 4.19 (brs, 3H), 6.98 (t, J=10 Hz, 1H)

EXAMPLE 15

Synthesis of ethyl8-chloro-6,7-difluoro-1-(3,5-difluoro-6-methylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 5 ml of chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.70g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 430 mg of 2-amino-3,5-difluoro-6-(methylamino)pyridine. Thesolution was concentrated under reduced pressure. To the residue wereadded 0.3 g of anhydrous potassium carbonate and 2 ml ofN,N-dimethylformamide, and the mixture was stirred at 90° C. for 10minutes and allowed to cool. The solution was separated by adding 30 mlof chloroform and 300 ml of distilled water, and the chloroform layerwas washed twice with 300 ml distilled water, dried over anhydrousmagnesium sulfate, concentrated under reduced pressure, and allowed tostand. The precipitate was collected by filtration, washed with ethanoland diisopropylether successively to obtain 784 mg of the title compoundas a colorless powder.

Melting point: 207 to 209° C.

¹ HNMR (CDCl₃) δ;

1.41 (t, J=7 Hz, 3H), 2.98 (d, J=5 Hz, 3H), 4.41 (q, J=7 Hz, 2H), 4.85(brs, 1H), 7.23 (dd, J=8 Hz, 9 Hz, 1H), 8.32 (dd, J=8 Hz, 10 Hz, 1H),8.50 (s, 1H)

EXAMPLE 16

Synthesis of8-chloro-6,7-difluoro-1-(3,5-difluoro-6-methylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 3 ml of a mixed solution (1:1, v/v) of 4 ml of 4N hydrochloric acidand 1 ml of acetic acid was added 510 mg of ethyl8-chloro-6,7-difluoro-1-(3,5-difluoro-6-methylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux with stirring for 2.5 hours.After adding 2 ml of distilled water, the mixture was allowed to cool,and the precipitate was collected by filtration and washed with ethanoland diisopropylether successively to obtain 454 mg of the title compoundas a gray powder.

Melting point: 236 to 242° C.

¹ HNMR (d₆ -DMSO) δ;

2.67 (d, J=5 Hz, 3H), 5.94 (brs, 1H), 7.06 (t, J=8 Hz, 1H), 7.45 (dd,J=10 Hz, 12 Hz, 1H), 8.41 (dd, J=9 Hz, 10 Hz, 1H), 8.72 (s, 1H)

EXAMPLE 17

Synthesis of7-(3-aminoazetidin-1-yl)-8-chloro-6-fluoro-1-(3,5-difluoro-6-methylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 400 mg of N,N-dimethylformamide were added 100 mg of8-chloro-6,7-difluoro-1-(3,5-difluoro-6-methylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 60 mg of 3-aminoazetidine dihydrochloride, and 120 mg ofN-methylpyrrolidine, and the mixture was stirred at 100° C. for 1 hour.After adding 0.5 ml of ethanol, the mixture was allowed to cool, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 102 mg of the title compound asa colorless powder.

Melting point: 222 to 227° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

2.77 (d, J=5 Hz, 3H), 3.75 (m, 1H), 4.07 (m, 2H), 4.67 (m, 2H), 7.19(brs, 1H), 7.88 (d, J=14 Hz, 1H), 7.95 (t, J=7 Hz, 1H), 8.70 (s, 1H)

REFERENCE EXAMPLE 10

Synthesis of 2-benzylamino-3,5,6-trifluoro-4-methylpyridine

To 2 ml of N-methylpyrrolidone were added 1.65 g of2,3,5,6-tetrafluoro-4-methylpyridine and 2.30 g of benzylamine, and themixture was stirred at 80° C. for 2 hours and allowed to cool. Afteradding 25 ml of chloroform, the mixture was washed three times with 300ml of distilled water. The chloroform layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to obtain thetitle compound in crude form.

REFERENCE EXAMPLE 11

Synthesis of 2-amino-3,5,6-trifluoro-4-methylpyridine

To 4 ml of methanol were added all amount of the crude2-benzylamino-3,5,6-trifluoro-4-methylpyridine as described abovetogether with 0.18 g of 10% palladium on carbon and 2 ml of acetic acid,and the mixture was hydrogenated at 50° C. for one day. The catalyst wasseparated by filtration, and the solvent and the like were distilled offunder reduced pressure to obtain 1.35 g of the title compound as acolorless solid.

¹ HNMR (CDCl₃) δ;

2.26 (t, J=2 Hz, 3H), 4.40 (brs, 2H)

REFERENCE EXAMPLE 12

Synthesis of2-amino-3,5-difluoro-6-(p-methoxybenzylamino)-4-methylpyridine

To 3 ml of N-methylpyrrolidone were added 1.35 g of2-amino-3,5,6-trifluoro-4-methylpyridine together with 3.0 g ofp-methoxybenzylamine, and the mixture was stirred under nitrogenatmosphere at 140° C. for 18 hours and allowed to cool. After adding 30ml of chloroform, the mixture was washed three times with 300 ml ofdistilled water. The chloroform layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wassubjected to chromatography (silica gel, 20 g; eluent:chloroform:n-hexane, 1:1, and then, chloroform) to obtain 0.90 g of thetitle compound as a pale yellow crude oil.

¹ HNMR (CDCl₃) δ;

2.15 (t, J=2 Hz, 3H), 3.80 (s, 3H), 4.11 (brs, 2H), 4.41 (brs, 1H), 4.48(m, 2H), 6.87 (d, J=8 Hz, 2H), 7.27 (d, J=8 Hz, 2H)

EXAMPLE 18

Synthesis of ethyl8-chloro-1-[3,5-difluoro-6-(p-methoxybenzylamino)-4-methylpyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 3 ml chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.78g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 0.90 g of2-amino-3,5-difluoro-6-(p-methoxybenzylamino)-4-methylpyridine. Thesolution was concentrated under reduced pressure, and to the residuewere added 1.3 g of anhydrous potassium carbonate and 3 ml ofN,N-dimethylformamide, and the mixture was stirred at 90° C. for 15minutes and allowed to cool. The solution was separated by adding 30 mlof chloroform and 300 ml of distilled water, and the chloroform layerwas washed twice with 300 ml of distilled water, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to obtain thetitle compound as a brown crude oil.

EXAMPLE 19

Synthesis of1-(6-amino-3,5-difluoro-4-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a mixed solution of 2.5 ml of 4N hydrochloric acid and 2.5 ml ofacetic acid was added all amount of the above described ethyl8-chloro-1-[3,5-difluoro-6-(p-methoxybenzylamino)-4-methylpyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux with stirring for 3 hours andallowed to cool and stand. To the residue was added 10 ml of distilledwater, and the solution was concentrated under reduced pressure. Theprocedure of adding 10 ml of ethanol and concentrating the solutionunder reduced pressure was repeated three times, and 6 ml of chloroformwas added to the residue, and the mixture was heated under reflux withstirring for 1 hour and allowed to cool. The precipitate was collectedby filtration, and washed with ethanol and diisopropylether successivelyto obtain 128 mg of the title compound as a colorless powder.

Melting point: 253 to 257° C.

¹ HNMR (d₆ -DMSO) δ;

2.24 (s, 3H), 6.67 (brs, 2H), 8.38 (t, J=9 Hz, 1H), 8.89 (s, 1H)

EXAMPLE 20

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-3,5-difluoro-4-methylpyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 280 mg of N,N-dimethylformamide were added 50 mg of1-(6-amino-3,5-difluoro-4-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 40 mg of 3-aminoazetidine dihydrochloride, and 120 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour.After adding 0.4 ml of ethanol, the mixture was allowed to cool. Theprecipitate was collected by filtration, and washed with ethanol anddiisopropylether successively to obtain 45 mg of the title compound as acolorless powder.

Melting point: 243 to 245° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

2.23 (s, 3H), 3.71 (m, 1H), 4.05 (m, 2H), 4.67 (m, 2H), 6.60 (brs, 2H),7.85 (d, J=14 Hz, 1H), 8.64 (s, 1H)

REFERENCE EXAMPLE 13

Synthesis of 4-(t-butylamino)-2,3,5,6-tetrafluoropyridine

To 100 ml of acetonitrile was added 24.5 g of pentafluoropyridine, andthe mixture was stirred in an ice bath simultaneously with the dropwiseaddition of 30 g of t-butylamine. When the mixture warmed to roomtemperature, 150 ml of chloroform was added, and the mixture was washedtwice with 800 ml of distilled water. The chloroform layer was driedover anhydrous magnesium sulfate and concentrated under reduced pressureto obtain 23 g of the title compound as a pale yellow oil.

REFERENCE EXAMPLE 14

Synthesis of 2-benzylamino-4-(t-butylamino)-3,5,6-trifluoropyridine

To 10 ml of N-methylpyrrolidone were added 6.8 g of4-(t-butylamino)-2,3,5,6-tetrafluoropyridine together with 7.2 g ofbenzylamine, and the mixture was stirred at 115° C. for one day andallowed to cool. After adding 40 ml of chloroform, the mixture waswashed three times with 400 ml of distilled water. The chloroform layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure to obtain about 8.0 g of the title compound as a darkgreen crude oil.

¹ HNMR (CDCl₃) δ;

1.39 (s, 9H), 4.16 (brs, 1H), 4.55 (brs, 2H), 4.48 (m, 2H), 7.35 (m, 5H)

REFERENCE EXAMPLE 15

Synthesis of 2-amino-4-(t-butylamino)-3,5,6-trifluoropyridine

To 13 ml of acetic acid were added 4.0 g of the crude2-benzylamino-4-(t-butyl)amino-3,5,6-trifluoropyridine as describedabove together with 0.43 g of 10% palladium on carbon, and the mixturewas hydrogenated at 60° C. for 6 hours. The catalyst was separated byfiltration, and the solvent and the like were distilled off underreduced pressure to obtain the title compound as a brown crude oil.

REFERENCE EXAMPLE 16

Synthesis of ethyl3-[(4-t-butylamino-3,5,6-trifluoropyridin-2-yl)amino]-2-(3-chloro-2,4,5-trifluorobenzoyI)acrylate

To 1.4 g of ethyl 3-chloro-2,4,5-trifluorobenzoyl-acetate were added 1.5g of acetic anhydride and 1.5 g of triethyl orthoformate, and themixture was heated under reflux for 2 hours. The solvent was distilledoff, and toluene was added to the residue for azeotropic distillation. 3ml of chloroform was added to the half of the residue, and 5 ml ofchloroform solution of 1 g of2-amino-3,5,6-trifluoro-4-(t-butylamino)pyridine was added dropwise tothe mixture with an ice cooling, then the mixture was stirred at roomtemperature for 2 hours. The solvent was distilled off, and the solidprecipitate was collected by filtration and washed with diethylether toobtain 1.14 g of the title compound.

EXAMPLE 21

Synthesis of ethyl1-(4-t-butylamino-3,5,6-trifluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 6 ml of N,N-dimethyl-formamide solution of 1.14 g of ethyl3-[(4-t-butylamino-3,5,6-trifluoropyridin-2-yl)amino]-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylatewas added 700 mg of potassium carbonate, and the mixture was stirred atroom temperature for 3.5 hours. The reaction solution was poured intoice water, and ethyl acetate was added for extraction. The organic layerwas separated and dried over magnesium sulfate, and solvent wasdistilled off. The solid content was collected by filtration to obtain1.25 g of the title compound as a colorless powder.

Melting point: 145 to 146° C.

¹ HNMR (CDCl₃) δ;

1.40 (t, J=7 Hz, 3H), 1.48 (s, 9H), 4.41 (q, J=7 Hz, 2H), 4.78 (1H,brs), 8.31 (t, J=9 Hz, 1H), 8.44 (1H, s)

EXAMPLE 22

Synthesis of1-(4-amino-3,5,6-trifluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 300 mg of ethyl1-(4-t-butylamino-3,5,6-trifluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylatewere added 3 ml of 12N hydrochloric acid and 0.5 ml of acetic acid, andthe mixture was heated under reflux for 1.5 hour. The reaction solutionwas allowed to cool, and the solid precipitated was collected byfiltration and washed with ethanol and diethylether successively toobtain 168 mg of the title compound as a colorless powder.

Melting point: 280 to 283° C.

¹ HNMR (d₆ -DMSO) δ;

7.54 (s, 1H), 8.38 (dd, J=9 Hz, 10 Hz, 1H), 8.98 (s, 1)

EXAMPLE 23

Synthesis of7-(3-aminoazetidin-1-yl)-1-(4-amino-3,5,6-trifluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 1 ml dimethylsulfoxide solution of 70 mg of 3-aminoazetidinedihydrochloride and 250 mg of triethylamine at 80° C. was added 150 mgof1-(4-amino-3,5,6-trifluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid with stirring, and the mixture was stirred at 80° C. for 1 hour.The reaction solution was allowed to cool and decanted withdiethylether. Ethanol was added to the residue to disperse the solidcontent, and the solid content was collected by filtration, washed withethanol, and dried to obtain 85 mg of the title compound as a paleyellow powder.

Melting point: decomposed at 230° C. or higher

¹ HNMR (d₆ -DMSO+TFA) δ;

4.05 (m, 1H), 4.45 (m, 2H), 4.77 (m, 2H), 7.50 (2H, brs), 7.93 (d, J=14Hz, 1H), 8.32 (brs, 2H), 8.80 (s, 1H)

REFERENCE EXAMPLE 17

Synthesis of 3,5-diamino-2-chloropyridine

The mixture of 2.19 g of iron powder, 5 ml of water, and 10 ml ofethanol was stirred at 80° C. for 2 minutes. After incremental additionof 1 ml concentrated hydrochloric acid, the mixture was stirred at thesame temperature until the solution became neutral. To the reactionsolution was incrementally added suspension of 1 g2-chloro-3,5-dinitropyridine in 5 ml ethanol, and the mixture wasstirred at 80° C. for 40 minutes. The reaction solution was allowed tocool, and the iron was removed by filtration with celite, and thesolvent of the filtrate was distilled off. Ethanol was added to theresidue to disperse the solid content, and the solid content wascollected by filtration to obtain 360 mg of the title compound.

REFERENCE EXAMPLE 18

Synthesis of ethyl3-[(5-amino-6-chloropyridin-3-yl)amino]-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate

To 1.4 g of ethyl 3-chloro-2,4,5-trifluorobenzoyl-acetate were added 1.5g of acetic anhydride and 1.5 g of triethyl orthoformate, and themixture was heated under reflux for 2 hours. The solvent was distilledoff, and toluene was added to the residue for azeotropic distillation. 3ml of chloroform was added to the half of the residue, and a solution of360 mg of 3,5-diamino-2-chloropyridine in 3 ml ethanol was addeddropwise to the mixture at room temperature and the mixture was stirredat room temperature for 30 minutes. The solvent was distilled off, andthe residue was purified by column chromatography to obtain 200 mg ofthe title compound.

EXAMPLE 24

Synthesis of ethyl1-(5-amino-6-chloropyridin-3-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To a solution of 180 mg ethyl3-[(5-amino-6-chloropyridin-3-yl)amino]-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylatein 3 ml N,N-dimethylformamide was added 57 mg of potassium carbonate,and the mixture was stirred at room temperature for 2 hours. Thereaction solution was poured into ice water, and extracted by addingethyl acetate. The organic layer was separated and dried over magnesiumsulfate, and the solvent was distilled off. The solid content wascollected by filtration to obtain 125 mg of the title compound as a paleyellow powder.

Melting point: 233 to 236° C.

¹ HNMR (CDCl₃) δ;

1.39 (t, J=7 Hz, 3H), 4.40 (q, J=7 Hz, 2H), 4.46 (brs, 2H), 7.04 (s,1H), 7.26 (s, 1H), 7.86 (s, 1H), 8.32 (t, J=9 Hz, 1H), 8.37 (s, 1H)

EXAMPLE 25

Synthesis of1-(5-amino-6-chloropyridin-3-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 100 mg of ethyl1-(5-amino-6-chloropyridin-3-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylatewas added 3 ml of concentrated hydrochloric acid, and the mixture washeated under reflux for 2 hours. The reaction solution was allowed tocool, and the solid precipitated was collected by filtration. The solidwas washed with ethanol to obtain 86 mg of the title compound as a paleyellow powder.

Melting point: 277 to 281° C.

¹ HNMR (d₆ -DMSO) δ;

7.37 (s, 1H), 7.86 (s, 1H), 8.41 (t, J=9 Hz, 1H), 8.69 (s, 1H)

EXAMPLE 26

Synthesis of7-(3-aminoazetidin-1-yl)-1-(5-amino-6-chloropyridin-3-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To dimethylsulfoxide solution 1 ml of 53 mg of 3-aminoazetidinedihydrochloride and 146 mg of triethylamine at 80° C. was added 80 mg of1-(5-amino-6-chloropyridin-3-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid with stirring, and the mixture was stirred at 80° C. for 1 hour.The reaction solution was allowed to cool and decanted withdiethylether. Ethanol was added to the residue to disperse the solidcontent, and the solid content was collected by filtration, washed withethanol, and dried to obtain 45 mg of the title compound as a paleyellow powder.

Melting point: 280° C. or higher

¹ HNMR (d₆ -DMSO) δ;

3.78 (m, 1H), 4.14 (m, 2H), 4.64 (m, 2H), 6.04 (br, 2H), 7.30 (s, 1H),7.75 (s, 1H), 7.89 (d, J=14 Hz, 1H), 8.49 (s, 1H)

REFERENCE EXAMPLE 19

Synthesis of 2,4-dichloro-5-fluoropyrimidine

25.3 g of 5-fluorouracil was fully mixed with 72.9 of phosphorpentachloride, and the mixture was gradually heated to 130° C. andreacted for 4 hours. (The reaction mixture became liquid in about 1hour, and the reaction proceeded at a high rate.) After adding 300 ml ofice water and 200 ml of chloroform, the mixture was stirred for 20minutes. The insoluble content was separated by filtration with celite,and the filtrate was separated. The chloroform layer was washed with 5%aqueous solution of sodium carbonate, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure to obtain 30.6 g of thetitle compound as a brown oil (which crystallized at a lowertemperature).

¹ HNMR (CDCl₃) δ; 8.49 (s, 1H)

REFERENCE EXAMPLE 20

Synthesis of 4-(t-butylamino)-2-chloro-5-fluoropyrimidine

To 20 ml of acetonitrile were added 6.4 g of2,4-dichloro-5-fluoropyrimidine and 7.0 g of t-butylamine, then themixture was stirred at 50° C. for 20 minutes. The solution wasconcentrated under reduced pressure, and separated by adding 40 ml ofdistilled water and 70 ml of chloroform. The chloroform layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The precipitated pale yellow crystals were dispersed indiisopropylether and collected by filtration to obtain 4.1 g of thetitle compound.

¹ HNMR (CDCl₃) δ;

1.51 (s, 9H), 5.07 (brs, 1H), 7.83 (d, J=3 Hz, 1H)

REFERENCE EXAMPLE 21

Synthesis of 2-benzylamino-4-(t-butylamino)-5-fluoropyrimidine

To 5 ml of N-methylpyrrolidone were added 1.8 g of4-(t-butylamino)-2-chloro-5-fluoropyrimidine and 4.0 g of benzylamine,and the mixture was stirred at 140° C. for 17 hours and separated byadding 300 ml of distilled water and 40 ml of chloroform. The chloroformlayer was washed twice with 300 ml of distilled water, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theprecipitated pale yellow crystals were dispersed in diisopropylether andcollected by filtration to obtain 1.9 g of the title compound.

¹ HNMR (CDCl₃) δ;

1.40 (s, 9H), 4.54 (d, J=6 Hz, 2H), 4.71 (brs, 1H), 5.06 (brs, 1H), 7.33(m, 5H), 7.65 (d, J=3 Hz, 1H)

REFERENCE EXAMPLE 22

Synthesis of 2-amino-4-(t-butylamino)-5-fluoropyrimidine

To 8 ml of acetic acid were added 1.00 g of2-benzylamino-4-(t-butylamino)-5-fluoropyrimidine together with 215 mgof 10% palladium on carbon, and the mixture was hydrogenated at 60° C.for ten days. The catalyst was separated by filtration, and the solventand the like were distilled off under reduced pressure. The procedure ofadding 10 ml of ethanol and concentrating under reduced pressure wasrepeated three times, and the residue was separated by columnchromatography (silica gel, 25 g; eluent: chloroform, and then,chloroform:methanol, 200:1), and the corresponding fractions werecollected and concentrated under reduced pressure to obtain 360 mg ofthe title compound as a pale gray solid.

¹ HNMR (CDCl₃) δ;

1.47 (s, 9H), 4.92 (brs, 1H), 5.57 (brs, 2H), 7.51 (d, J=3 Hz, 1H)

EXAMPLE 27

Synthesis of ethyl1-[4-(t-butylamino)-5-fluoropyrimidin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 3 ml of chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 210mg of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 340 mg of 2-amino-4-(t-butylamino)-5-fluoropyrimidine. Thesolution was concentrated under reduced pressure. To the residue wereadded 550 mg of anhydrous potassium carbonate and 2 ml ofN,N-dimethylformamide, and the mixture was stirred at 90° C. for 1 hourand 10 minutes and allowed to cool. The solution was separated by adding30 ml of chloroform and 300 ml of distilled water, and the chloroformlayer was washed twice with 300 ml of distilled water, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was separated by column chromatography (silica gel, 16 g;eluent: chloroform:methanol, 200:1), and the corresponding fractionswere collected and concentrated under reduced pressure. To the residuewas added 0.5 ml of ethanol, and the precipitate was collected byfiltration and washed with ethanol and diisopropylether successively toobtain 98 mg of the title compound as a colorless powder.

Melting point: 201 to 205° C.

¹ HNMR (CDCl₃) δ;

1.38 (t, J=7 Hz, 3H), 1.43 (s, 9H), 4.39 (q, J=7 Hz, 2H), 5.30 (brs,1H), 8.02 (d, J=3 Hz, 1H), 8.24 (t, J=9 Hz, 1H), 8.90 (s, 1H)

EXAMPLE 28

Synthesis of1-(4-amino-5-fluoropyrimidin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a mixed solution (1:1, v/v) of 0.4 ml of 4N hydrochloric acid and 1ml of acetic acid was added 90 mg of ethyl1-[4-(t-butylamino)-5-fluoropyrimidin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux with stirring for 3 and halfhours and allowed to cool. The precipitate was collected by filtration,and washed with ethanol and diisopropylether successively to obtain 48mg of the title compound as a colorless powder.

Melting point: 242 to 246° C.

¹ HNMR (d₆ -DMSO) δ;

8.04 (brs, 2H), 8.33 (d, J=3 Hz, 1E), 8.34 (t, J=9 Hz, 1H), 9.02 (s, 1H)

EXAMPLE 29

Synthesis of7-(3-aminoazetidin-1-yl)-1-(4-amino-5-fluoropyrimidin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 100 mg of N,N-dimethylformamide were added 25 mg of1-(4-amino-5-fluoropyrimidin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 20 mg of 3-aminoazetidine dihydrochloride, and 50 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour.After adding 0.2 ml of ethanol, the mixture was allowed to cool, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 10 mg of the title compound as acolorless powder.

Melting point: 269 to 271° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.73 (m, 1H), 4.07 (m, 2H), 4.67 (m, 2H), 7.81 (d, J=15 Hz, 1H), 7.95(brs, 1H), 8.29 (d, J=3 Hz, 1H), 8.83 (s, 1H)

REFERENCE EXAMPLE 23

Synthesis of 2-amino-3,5-difluoro-6-methoxypyridine

To 1 ml of methanol were added 500 mg of 2-amino-3,5,6-trifluoropyridinetogether with 800 mg of 28% sodium methoxide/methanol solution, and themixture was stirred at 70° C. for 3 and half hours, and allowed to cool.After adding 25 ml of chloroform, the mixture was washed with 5 ml ofdistilled water. The chloroform layer was dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure to obtain the titleproduct.

EXAMPLE 30

Synthesis of ethyl8-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 3 ml chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.78g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 2-amino-3,5-difluoro-6-methoxypyridine until completion of theconversion into the aminoacrylate form was confirmed by monitoring thereaction by TLC. The solution was concentrated under reduced pressure,and to the residue were added 0.80 g of anhydrous potassium carbonateand 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C.for 15 minutes and allowed to cool. The solution was separated by adding30 ml of chloroform and 300 ml of distilled water, and the chloroformlayer was washed twice with 300 ml of distilled water, dried overanhydrous magnesium sulfate, concentrated under reduced pressure, andallowed to stand. The precipitate was collected by filtration, washedwith ethanol to obtain 615 mg of the title compound as a pale brownpowder.

Melting point: 140 to 143° C.

¹ HNMR (CDCl₃) δ;

1.41 (t, J=7 Hz, 3H), 3.99 (s, 3H), 4.41 (q, J=7 Hz, 2H), 7.44 (t, J=8Hz, 1H), 8.33 (dd, J=8 Hz, 10 Hz), 8.45 (s, 1H)

EXAMPLE 31

Synthesis of8-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a mixed solution of 1 ml of 4N hydrochloric acid and 1 ml of aceticacid was added 385 mg of ethyl8-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture heated under reflux with stirring for 30 minutes. Afteradding 2 ml of distilled water, the solution was allowed to cool andstand. The precipitate was collected by filtration, and washed withethanol and diisopropylether successively to obtain 297 mg of the titlecompound as a colorless powder.

Melting point: 205 to 210° C.

¹ HNMR (d₆ -DMSO) δ;

3.92 (s, 3H), 8.39 (t, J=9 Hz, 1H), 8.40 (t, J=9 Hz, 1H), 9.03 (s, 1H)

EXAMPLE 32

Synthesis of7-(3-aminoazetidin-1-yl)-8-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 500 mg of acetonitrile were added 75 mg of8-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 65 mg of 3-aminoazetidine dihydrochloride, and 150 mg ofN-methylpyrrolidine, and the mixture was heated under reflux for 1 hour.The precipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 28 mg of the title compound as acolorless powder. 5 Melting point: 171 to 175° C.

¹ HNMR (d₆ -DMSO) δ;

3.70 (m, 1H), 3.91 (s, 3H), 4.05 (m, 2H), 4.66 (m, 2H), 7.88 (d, J=14Hz, 1H), 8.34 (t, J=9 Hz, 1H), 8.79 (s, 1H)

EXAMPLE 33

Synthesis of ethyl7-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3-carboxylate

To 10 ml chloroform solution of ethyl3-ethoxy-2-(2,6-dichloro-5-fluoronicotinoyl)acrylate prepared from 1.25g of ethyl 2,6-dichloro-5-fluoronicotinoylacetate by normal process wasadded the crude 2-amino-3,5-difluoro-6-methoxypyridine until completionof the conversion into the aminoacrylate form was confirmed bymonitoring the reaction by TLC. The solution was concentrated underreduced pressure, and to the residue were added 2.0 g of anhydrouspotassium carbonate and 4 ml of N,N-dimethylformamide, and the mixturewas stirred at 90° C. for 20 minutes and allowed to cool. The solutionwas separated by adding 50 ml of chloroform and 300 ml of distilledwater, and the chloroform layer was washed twice with 300 ml ofdistilled water, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The precipitate was dispersed inethanol, collected by filtration, and washed with ethanol anddiisopropylether successively to obtain 1010 mg of the title compound asa pale brown powder.

Melting point: 208 to 212° C.

¹ HNMR (CDCl₃) δ;

1.42 (t, J=7 Hz, 3H), 4.04 (s, 3H), 4.40 (q, J=7 Hz, 2H), 7.50 (t, J=8Hz, 1H), 8.48 (d, J=7 Hz 1H ), 8.69 (s, 1H)

EXAMPLE 34

Synthesis of7-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3-carboxylicacid

To 1.5 ml of a mixed solution (1:1, v/v) of 3N hydrochloric acid andacetic acid was added 300 mg of ethyl7-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3-carboxylate,and the mixture was heated under reflux with stirring for 1 hour. Afteradding 2 ml of distilled water, the mixture was heated under reflux for10 minutes and allowed to cool, and the precipitate was collected byfiltration and washed with ethanol and diisopropylether successively toobtain 248 mg of the title compound as a pale brown powder.

Melting point: 220 to 225° C.

¹ HNMR (d₆ -DMSO) δ;

3.97 (s, 3E), 8.42 (t, J=9 Hz, 1H), 8.76 (d, J=7 Hz, 1H), 9.21 (s, 1H)

EXAMPLE 35

Synthesis of7-[(3S)-3-aminopyrrolidin-1-yl]-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3-carboxylicacid

To 400 mg of N,N-dimethylformamide were added 82 mg of 7-chloro-l-(3,5-difluoro-6-methoxypyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3-carboxylicacid, 70 mg of (3S)-3-aminopyrrolidine, and 60 mg of triethylamine, andthe mixture was heated under reflux at 80° C. for 30 minutes. Afteradding 2.5 ml of ethanol, the mixture was heated under reflux for 5minutes and allowed to cool, and the precipitate was collected byfiltration, and washed with ethanol and diisopropylether successively toobtain 102 mg of the title compound as a pale brown powder.

Melting point: 231 to 233° C.

¹ HNMR (d₆ -DMSO) δ;

1.65 (m, 1H), 1.93 (m, 1H), 3.95 (s, 3H), 8.02 (d, J=13 Hz, 1H), 8.35(t, J=9 Hz, 1H), 8.94 (s, 1H) (Part of signals overlapped with theproton of water, and were undistinguishable.)

EXAMPLE 36

Synthesis of 7-[(3S,4S)-3-amino-4-methylpyrrolidin-1-yl]-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3-carboxylicacid

To 500 mg of N,N-dimethylformamide were added 85 mg of7-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3-carboxylicacid, 70 mg of (3S,4S)-3-amino-4-methylpyrrolidine dihydrochloride, and150 mg of triethylamine, and the mixture was heated under reflux at 80°C. for 30 minutes. After adding 2.5 ml of ethanol, the mixture washeated under reflux for 5 minutes and allowed to cool, and theprecipitate was collected by filtration, and washed with ethanol anddiisopropylether successively to obtain 105 mg of the title compound asa colorless powder.

Melting point: 226 to 229° C.

¹ HNMR (d₆ -DMSO) δ;

0.94 (brd, J=8 Hz, 3H), 2.16 (m, 1H), 3.95 (s, 3H), 8.02 (d, J=13 Hz,1H), 8.35 (m, 1H), 8.95 (s, 1H) (Part of signals overlapped with theproton of water, and were undistinguishable.)

EXAMPLE 37

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a mixed solution of 3.5 ml of 4N hydrochloric acid and 3.5 ml ofacetic acid was added 1.38 g of ethyl8-bromo-1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux with stirring for 5 hours. Afteradding 5 ml of distilled water, the mixture was allowed to cool, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 1.10 g of the title compound asa colorless powder.

Melting point: 272 to 278° C.

¹ HNMR (d₆ -DMSO) δ;

6.80 (s, 2H), 7.99 (t, J=9 Hz, 1H), 8.38 (t, J=9 Hz, 1H), 8.93 (s, 1H)

EXAMPLE 38

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a mixed solution of 0.5 ml of 4N hydrochloric acid and 0.5 ml ofacetic acid was added 235 mg of ethyl1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux with stirring for 7 hours. Afteradding 1 ml of distilled water, the mixture was allowed to cool, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 182 mg of the title compound asa colorless powder.

Melting point: 280° C. or higher

¹ HNMR (d₆ -DMSO) δ;

6.81 (brs, 2H), 8.04 (t, J=9 Hz, 1H), 8.23 (m, 1H), 8.98 (s, 1H)

EXAMPLE 39

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 300 mg of N,N-dimethylformamide were added 105 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour.After adding 0.3 ml of ethanol, the mixture was allowed to cool, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 79 mg of the title compound as acolorless powder.

Melting point: 258 to 264° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.73 (m, 1H), 4.06 (m, 2H), 4.69 (m, 2H), 6.75 (brs, 2H), 7.89 (d, J=14Hz, 1H), 7.94 (t, J=9 Hz, 1H), 8.70 (s, 1H)

EXAMPLE 40

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-3,5-difluoropyridin-2-yl)-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 270 mg of N,N-dimethylformamide were added 90 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 50 mg of 3-aminoazetidine dihydrochloride, and 110 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour.After adding 0.3 ml of ethanol, the mixture was allowed to cool, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 70 mg of the title compound as acolorless powder.

Melting point: 256 to 260° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.76 (m, 1H), 3.94 (m, 2H), 4.44 (m, 2H), 6.74 (brs, 2H), 7.78 (d, J=13Hz, 1H), 7.99 (t, J=9 Hz, 1H), 8.73 (s, 1H)

EXAMPLE 41

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6-fluoro-7-(3-methylaminoazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 800 mg of N,N-dimethylformamide were added 260 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 130 mg of 3-methylaminoazetidine dihydrochloride, and 300 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour.After adding 0.5 ml of ethanol, the mixture was allowed to cool, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 247 mg of the title compound asa pale yellow powder.

Melting point: 238 to 245° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

2.21 (s, 3H), 3.46 (m, 1H), 4.12 (m, 2H), 4.63 (m, 2H), 6.75 (brs, 2H),7.88 (d, J=14 Hz, 1H), 7.94 (t, J=9 Hz, 1H), 8.70 (s, 1H)

EXAMPLE 42

Synthesis of7-[3-(ethylamino)azetidin-1-yl]-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 310 mg of N,N-dimethylformamide were added 100 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 70 mg of 3-(ethylamino)azetidine dihydrochloride, and 150 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 15minutes. After adding 1 ml of ethanol, the mixture was allowed to cool,and the precipitate was collected by filtration and washed with ethanoland diisopropylether successively to obtain 107 mg of the title compoundas a colorless powder.

Melting point: 241 to 245° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

0.98 (t, J=7 Hz, 3H), 2.49 (q, J=7 Hz, 2H), 3.55 (m, 1H), 4.14 (m, 2H),4.66 (m, 2H), 6.76 (brs, 2H), 7.86 (d, J=14 Hz, 1H), 7.95 (t, J=9 Hz,1H), 8.69 (s, 1H)

EXAMPLE 43

Synthesis of7-[3-(dimethylamino)azetidin-1-yl]-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 310 mg of N,N-dimethylformamide were added 100 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 100 mg of 3-(dimethylamino)azetidine dihydrochloride, and 150 mgof N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15minutes. After adding 1 ml of ethanol, the mixture was allowed to cool,and the precipitate was collected by filtration and washed with ethanoland diisopropylether successively to obtain 87 mg of the title compoundas a colorless powder.

Melting point: 283 to 287° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

2.07,(s, 6H), 3.03 (m, 1H), 4.24 (m, 2H), 4.55 (m, 2H), 6.77 (brs, 2H),7.86 (d, J=14 Hz, 1H), 7.95 (t, J=9 Hz, 1H), 8.70 (s, 1H)

EXAMPLE 44

Synthesis of7-[3-(aminomethyl)azetidin-1-yl]-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 280 mg of N,N-dimethylformamide were added 80 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 100 mg of 3-(aminomethyl)azetidine dihydrochloride, and 200 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 25minutes. After adding 0.5 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 42 mg of the titlecompound as a colorless powder.

Melting point: 249 to 254° C.

¹ HNMR (d₆ -DMSO) δ;

2.67 (m, 1H), 2.80 (m, 2H), 4.21 (m, 2H), 4.49 (m, 2H), 6.73 (brs, 2H),7.80 (d, J=14 Hz, 1H), 7.93 (t, J=10 Hz, 1H), 8.56 (s, 1H)

REFERENCE EXAMPLE 24

Synthesis of 4-amino-3-chloro-2,5,6-trifluoropyridine

To 100 ml of acetonitrile was dissolved 20.5 g of3-chloro-2,4,5,6-tetrafluoropyridine, and 30 ml of 25% aqueous solutionof ammonia was added in three portions while the mixture was stirred andcooled with water, and the stirring was continued for another 30minutes. The solution was concentrated under reduced pressure. Afteradding 200 ml of chloroform to the solid residue, the solution waswashed with 50 ml of distilled water. The chloroform layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure, and the precipitate was collected by filtration to obtain 16.6g of the title compound as colorless flake crystals.

REFERENCE EXAMPLE 25

Synthesis of 4-bromo-3-chloro-2,5,6-trifluoropyridine To 45 ml ofacetonitrile was dissolved 9.4 g of4-amino-3-chloro-2,5,6-trifluoropyridine, and 7.5 g of t-butylnitritewas added dropwise in 25 minites stirring at 45° C., and the mixture washeated under reflux for 40 minutes and concentrated under reducedpressure. The residue was separated by adding 150 ml of chloroform and100 ml of 2N hydrochloric acid, and the chloroform layer was washed with20 ml of distilled water. The chloroform layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to obtain 10.2g of the title compound as pale yellow oil.

REFERENCE EXAMPLE 26

Synthesis of 4-bromo-2-(t-butylamino)-5-chloro-3,6-difluoropyridine

To 40 ml of acetonitrile was dissolved 10.2 g of4-bromo-3-chloro-2,5,6-trifluoropyridine and 10.5 g of t-butylamine, andthe mixture was heated under reflux for 1 hour and the solvent and thelike were distilled off under reduced pressure. To the residue was added80 ml of chloroform and the mixture was washed with 50 ml of distilledwater. The chloroform layer was dried over anhydrous magnesium sulfateand concentrated under reduced pressure to obtain 12.8 g of the titlecompound as reddish orange oil.

REFERENCE EXAMPLE 27

Synthesis of 2-(t-butylamino)-5-chloro-3,6-difluoropyridine

To 30 ml of methanol were added 12.8 g of4-bromo-2-(t-butylamino)-5-chloro-3,6-difluoropyridine and 2.5 g oftriethylamine together with 0.57 g of 10% palladium on carbon, and themixture was hydrogenated at 50° C. for 5 days. The catalyst wasseparated by filtration, and the solvent and the like were distilled offunder reduced pressure. To the residue was added 80 ml of chloroform,and the mixture was washed with 70 ml of distilled water, and thechloroform layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain 9.3 g of the titlecompound as a brown oil.

REFERENCE EXAMPLE 28

Synthesis of 2-benzylamino-6-(t-butylamino)-3-chloro-5-fluoropyridine

To 10 ml of N-methylpyrrolidone was added 6.8 g of2-(t-butylamino)-5-chloro-3,6-difluoropyridine together with 8.0 g ofbenzylamine, and the mixture was stirred at 150° C. for one day, andallowed to cool. After 80 ml of chloroform, the mixture was washed threetimes with 300 ml of distilled water. The chloroform layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was subjected to column chromatography (silicagel, 100 g; eluent: chloroform:n-hexane, 1:1) to obtain about 7.0 g ofthe title compound as a pale brown crude oil.

REFERENCE EXAMPLE 29

Synthesis of 2-amino-6-(t-butylamino)-3-chloro-5-fluoropyridine and2-amino-6-(t-butylamino)-5-fluoropyridine To a mixed solution of 18 mlmethanol and 1.4 g concentrated hydrochloric acid were added 3.1 g of2-benzylamino-6-(t-butylamino)-3-chloro-5-fluoropyridine together with0.33 g of 10% palladium on carbon, and the mixture was hydrogenated at30° C. for 1 hour. The catalyst was separated by filtration, and thesolvent and the like were distilled off under reduced pressure. To theresidue was added 50 ml of chloroform, and the mixture was washed with10 ml of 6% aqueous solution of sodium hydroxide, and the chloroformlayer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was subjected to column chromatography(silica gel, 40 g; eluent: chloroform:n-hexane, 3:1 and then 1:1) toobtain 1.35 g of 2-amino-6-(t-butylamino)-3-chloro-5-fluoropyridine as apale brown oil, and 0.32 g of 2-amino-6-(t-butylamino)-5-fluoropyridineas a brown oil.

2-amino-6-(t-butylamino)-3-chloro-5-fluoropyridine

¹ HNMR (CDCl₃) δ;

1.44 (s, 9H), 4.32 (brs, 1H), 4.37 (brs, 1H), 7.02 (d, J=10 Hz, 1H)

2-amino-6-(t-butylamino)-5-fluoropyridine

¹ HNMR (CDCl₃) δ;

1.46 (s, 9H), 3.99 (brs, 1H), 4.30 (brs, 1H), 5.61 (dd, J=2 Hz, 8 Hz,1H), 6.91 (dd, J=8 Hz, 11 Hz, 1H)

EXAMPLE 45

Synthesis of ethyl1-[6-(t-butylamino)-3-chloro-5-fluoropyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 3 ml chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.84g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 0.65 g of 2-amino-6-(t-butylamino)-3-chloro-5-fluoropyridine. Thesolution was concentrated under reduced pressure to obtain yellow solidresidue. To this residue were added 0.7 g of anhydrous potassiumcarbonate and 3 ml of N,N-dimethylformamide, and the mixture was stirredat 90° C. for 25 minutes and allowed to cool. The solution was separatedby adding 40 ml of chloroform and 300 ml of distilled water, and thechloroform layer was washed twice with 300 ml of distilled water, driedover anhydrous magnesium sulfate, concentrated under reduced pressure,and allowed to stand. The precipitate was collected by filtration,washed with ethanol and diisopropylether successively to obtain 1.06 gof the title compound as a pale yellow powder.

Melting point: 210 to 213° C.

¹ HNMR (CDCl₃) δ;

1.38 (s, 9H), 1.41 (t, J=7 Hz, 3H), 4.41 (q, J=7 Hz, 2H), 4.84 (brs,1H), 7.32 (d, J=lOHz, 1H), 8.32 (dd, J=8 Hz, 10 Hz, 1H), 8.45 (s, 1H)

EXAMPLE 46

Synthesis of1-(6-amino-3-chloro-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a mixed solution (1:1) of 2.5 ml of 4N hydrochloric acid and aceticacid was added 600 mg of ethyl1-[6-(t-butylamino)-3-chloro-5-fluoropyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux with stirring for 4.5 hours.After adding 2 ml of distilled water, the solution was allowed to cooland the precipitate was collected by filtration and washed with ethanoland diisopropylether successively to obtain 458 mg of the title compoundas a pale yellow powder.

Melting point: 280° C. or higher

¹ HNMR (d₆ -DMSO) δ;

7.10 (brs, 2H), 7.99 (d, J=10 Hz, 1H), 8.40 (t, J=10 Hz, 1H), 8.89 (s,1H)

EXAMPLE 47

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-3-chloro-5-fluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 300 mg of N,N-dimethylformamide were added 100 mg of1-(6-amino-3-chloro-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg ofN-methylpyrrolidone, and the mixture was stirred at 90° C. for 30minutes. After adding 0.3 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 95 mg of the titlecompound as a colorless powder.

Melting point: 268 to 270° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.71 (m, 1H), 4.08 (m, 2H), 4.67 (m, 2H), 7.04 (brs, 2H), 7.87 (d, J=14Hz, 1H), 7.94 (d, J=10 Hz, 1H), 8.62 (s, 1H)

EXAMPLE 48

Synthesis of1-(6-amino-3-chloro-5-fluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-methylaminoazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 300 mg of N,N-dimethylformamide were added 103 mg of1-(6-amino-3-chloro-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 85 mg of 3-methylaminoazetidine dihydrochloride, and 150 mg ofN-methylpyrrolidone, and the mixture was stirred at 85° C. for 30minutes. After adding 0.3 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 98 mg of the titlecompound as a colorless powder.

Melting point: 277 to 280° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

2.20 (s, 3H), 3.45 (m, 1H), 4.13 (m, 2H), 4.64 (m, 2H), 7.04 (brs, 2H),7.87 (d, J=14 Hz, 1H), 7.94 (d, J=10 Hz, 1H), 8.62 (s, 1H)

EXAMPLE 49

Synthesis of ethyl1-[6-(t-butylamino)-5-fluoropyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 2 ml chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.56g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 0.42 g of 2-amino-6-(t-butylamino)-5-fluoropyridine. The solutionwas concentrated under reduced pressure to obtain yellow solid residue.To this residue were added 0.6 g of anhydrous potassium carbonate and1.5 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C.for 20 minutes and allowed to cool. The solution was separated by adding40 ml of chloroform and 300 ml of distilled water, and the chloroformlayer was washed twice with 300 ml of distilled water, dried overanhydrous magnesium sulfate, concentrated under reduced pressure,supplemented with 2 ml of ethanol, and allowed to stand. The precipitatewas collected by filtration, washed with ethanol and diisopropylethersuccessively to obtain 0.48 g of the title compound as a pale yellowpowder.

Melting point: 207 to 210° C.

¹ HNMR (CDCl₃) δ;

1.37 (s, 9H), 1.40 (t, J=7 Hz, 3H), 4.40 (q, J=7 Hz, 2H), 4.82 (brs,1H), 6.52 (dd, J=3 Hz, 8 Hz, 1H), 7.25 (dd, J=8 Hz, 10 Hz, 1H), 8.31(dd, J=8 Hz, 10 Hz, 1H), 8.61 (s, 1H)

EXAMPLE 50

Synthesis of1-(6-amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 2,ml of mixed solution (1:1) of 4N hydrochloric acid and acetic acidwas added 450 mg of ethyl1-[6-(t-butylamino)-5-fluoropyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux with stirring for 3 hours. Afteradding 1 ml of distilled water, the mixture was allowed to cool, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 342 mg of the title compound asa colorless powder.

Melting point: 232 to 235° C.

¹ HNMR (d₆ -DMSO) δ;

6.87 (brs, 2H), 6.91 (dd, J=3 Hz, 8 Hz, 1H), 7.64 (dd, J=8 Hz, 11 Hz,1H), 8.36 (t, J=9 Hz, 1H), 8.77 (s, 1H)

EXAMPLE 51

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-5-fluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 270 mg of N,N-dimethylformamide were added 55 mg of1-(6-amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 70 mg of 3-aminoazetidine dihydrochloride, and 80 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 15minutes. After adding 0.3 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 62 mg of the titlecompound as a colorless powder.

Melting point: 250 to 254° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.71 (m, 1H), 4.05 (m, 2H), 4.67 (m, 2H), 6.78 (dd, J=3 Hz, 8 Hz, 1),6.80 (brs, 2H), 7.60 (dd, J=8 Hz, 10 Hz, 1H), 7.85 (d, J=14 Hz, l), 8.60(s, 1H)

EXAMPLE 52

Synthesis of1-(6-amino-5-fluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-methylaminoazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 300 mg of N,N-dimethylformamide were added 101 mg of1-(6-amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 85 mg of 3-methylaminoazetidine dihydrochloride, and 150 mg ofN-methylpyrrolidine, and the mixture was stirred at 85° C. for 30minutes. After adding 0.3 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 82 mg of the titlecompound as a colorless powder.

Melting point: 252 to 255° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

2.21 (s, 3H), 3.46 (m, 1H), 4.13 (m, 2H), 4.62 (m, 2H), 6.78 (m, 1H),6.81 (brs, 2H), 7.60 (dd, J=8 Hz, 10 Hz, 1H), 7.84 (d, J=14 Hz, 1H),8.60 (s, 1H)

REFERENCE EXAMPLE 30

Synthesis of N-(3-chloro-2,5,6-trifluoropyridin-4-yl)phthalimide

To a mixed solution of 40 ml dichloromethane and 20 mlN,N-methylformamide were added 18.5 g of3-chloro-2,4,5,6-tetrafluoropyridine and 20.5 g potassium phthalimide,and the mixture was stirred at 40° C. for one day. After adding 40 ml ofchloroform, the mixture was washed twice with 500 ml of distilled waterand once with 500 ml of 0.5% aqueous solution of sodium hydroxide. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The precipitate was dispersed indiisopropylether, and collected by filtration to obtain 32.0 g of thetitle compound as a colorless powder.

REFERENCE EXAMPLE 31

Synthesis ofN-[2-(t-butylamino)-5-chloro-3,6-difluoropyridin-4-yl]phthalimide

To 150 ml of acetonitrile was added 30.0 g ofN-(3-chloro-2,5,6-trifluoropyridin-4-yl)phthalimide together with 42.2 gof t-butylamine, and the mixture was heated under reflux with stirringfor 30 minutes. The solution was concentrated under reduced pressure,then 200 ml of chloroform was added, and washed with 100 ml of distilledwater. The organic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain about the title compoundas colorless solid residue.

REFERENCE EXAMPLE 32

Synthesis of N-(2-amino-5-chloro-3,6-difluoropyridin-4-yl)phthalimide

To 80 ml of trifluoroacetic acid was added all amount of theN-[2-(t-butylamino)-5-chloro-3,6-difluoropyridin-4-yl]phthalimide, andthe mixture was stirred at 70° C. for 5 and half hours. The solution wasconcentrated under reduced pressure. The precipitate was dispersed inchloroform, and collected by filtration to obtain 19.5 g of the titlecompound as a colorless powder.

REFERENCE EXAMPLE 33

Synthesis of N-(2,5-dichloro-3,6-difluoropyridin-4-yl)phthalimide

To 80 ml of acetonitrile was added 21.3 g ofN-(2-amino-5-chloro-3,6-difluoropyridin-4-yl)phthalimide together with14.0 g of cupric chloride, and the mixture was stirred at roomtemperature simultaneously with the dropwise addition of 15.8 g oft-butylnitrite dissolved in 30 ml acetonitrile in 10 minites. Themixture was stirred at 60° C. for 1 hour, and concentrated under reducedpressure. The residue was separated by adding 500 ml of chloroform and250 ml of 2N hydrochloric acid, and the chloroform layer was washed with50 ml of distilled water. The chloroform layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. Theprecipitate was dissolved and collected by filtration to obtain 16.2 gof the title compound as a colorless powder.

REFERENCE EXAMPLE 34

Synthesis of 4-amino-2,5-dichloro-3,6-difluoropyridine

To a mixed solution of 100 ml chloroform and 40 ml methanol was added16.2 g of N-(2,5-dichloro-3,6-difluoropyridin-4-yl)phthalimide togetherwith 20 ml of 25% aqueous solution of ammonia, and the mixture wasstirred at room temperature for 30 minutes. The solution wasconcentrated under reduced pressure, and after adding 150 ml ofchloroform to the residue, the mixture was washed with 20 ml of 15%aqueous solution of ammonia, and then, with 10 ml of distilled water.The chloroform layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain 4.55 g of the titlecompound as a colorless powder.

REFERENCE EXAMPLE 35

Synthesis of 4-amino-2,5-difluoropyridine

To 40 ml of methanol were added 4.5 g of4-amino-2,5-dichloro-3,6-difluoropyridine and 4.5 g of triethylaminetogether with 0.40 g of 10% palladium carbon, and the mixture washydrogenated at 50° C. for 12 days. The catalyst was separated byfiltration, and the solvent and the like were distilled off underreduced pressure. To the residue was added 100 ml of chloroform, and themixture was washed with 10 ml of distilled water. The chloroform layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure. To the residue were added 1.5 g of triethylamine, 0.35g of 10% palladium on carbon, and 30 ml of methanol, and the mixture washydrogenated at 50° C. for 41 hours. The catalyst was separated byfiltration, and the solvent and the like were distilled off underreduced pressure. To the residue was added 100 ml of chloroform, and themixture was washed with 10 ml of distilled water. The chloroform layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure to obtain 2.67 g of the title compound as precipitateas a colorless solid.

REFERENCE EXAMPLE 36

Synthesis of 2-benzylamino-4-amino-5-fluoropyridine

To 1 ml of N-methylpyrrolidone was added 410 mg of4-amino-2,5-difluoropyridine together with 930 mg of benzylamine, andthe mixture was allowed to react in nitrogen atmosphere at 150° C. for 3days and allowed to cool. After adding 30 ml of chloroform, the mixturewas washed twice with 300 ml of distilled water. The chloroform layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was subjected to column chromatography(silica gel, 15 g; eluent:chloroform:methanol, 1:0 and then, 50:1) toobtain 400 mg of the title compound as a colorless solid.

¹ HNMR (CDCl₃) δ;

4.06 (brs, 2H), 4.40 (d, J=6 Hz, 2H), 4.60 (brs, 1H), 5.69 (d, J=6 Hz,1H), 7.33 (m, 5H), 7.75 (d, J=3 Hz, 1H)

REFERENCE EXAMPLE 37

Synthesis of 2,4-diamino-5-fluoropyridine hydrochloride

To 4 ml of methanol having added 400 mg of concentrated hydrochloricacid added thereto was added 350 mg of2-benzylamino-4-amino-5-fluoropyridine together with 50 mg of 10%palladium on carbon, and the mixture was hydrogenated at 40° C. for 2days. The catalyst was separated by filtration, and the solvent and thelike were distilled off under reduced pressure. Procedure of adding 10ml of distilled water to the residue and concentrating under reducedpressure was repeated 4 times, and the procedure of adding 10 ml ofethanol and concentrating under reduced pressure was repeated twice. 260mg of the title compound was obtained as a residue in the form of ayellowish orange paste.

REFERENCE EXAMPLE 38

Synthesis of ethyl3-(4-amino-5-fluoropyridin-2-yl)amino-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylateand ethyl3-(2-amino-5-fluoropyridin-4-yl)amino-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate

To 1.2 ml chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.34g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 0.25 g of 2,4-diamino-5-fluoropyridine hydrochloride together with0.28 g of N-methylpyrrolidine. The solution was concentrated underreduced pressure, and to the residue were added 0.52 g of anhydrouspotassium carbonate and 0.8 ml of N,N-dimethylformamide, and the mixturewas stirred at 90 C for 15 minutes and allowed to cool. The solution wasseparated by adding 20 ml of chloroform and 100 ml of distilled water,and the chloroform layer was washed with 100 ml of distilled water,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to column chromatography (silicagel, 14 g; eluent: chloroform:methanol, 1:0, and then, 100:1), and thefraction containing the main product was concentrated under reducedpressure. The precipitate was dispersed in ethanol, collected byfiltration, and washed with ethanol and diisopropylether successively toobtain 1.06 g of the title mixture (1:1 in NMR) as a pale brown powder.

EXAMPLE 53

Synthesis of ethyl1-(4-amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 150 mg of the mixture of ethyl3-(4-amino-5-fluoropyridin-2-yl)amino-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylateand ethyl3-(2-amino-5-fluoropyridin-4-yl)amino-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylatewere added 230 mg of anhydrous potassium carbonate and 450 mg ofN,N-dimethylformamide, and the mixture was stirred at 100° C. for 20minutes and allowed to cool. The solution was separated by adding 20 mlof chloroform and 100 ml of distilled water, and the chloroform layerwas washed with 100 ml of distilled water, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to column chromatography (silica gel, 3.2 g; eluent:chloroform:methanol, 100:1), and the fraction containing the mainproduct was concentrated under reduced pressure to obtain 35 mg of thetitle compound as a yellow solid residue.

Melting point: 140 to 148° C.

¹ HNMR (CDCl₃) δ;

1.38 (t, J=7 Hz, 3H), 4.37 (q, J=7 Hz, 2H), 4.78 (brs, 2H), 6.78 (d, J=6Hz, 1H), 8.11 (d, J=3 Hz, 1H), 8.27 (dd, J=8 Hz, 10 Hz, 1H), 8.55 (s,1H)

EXAMPLE 54

Synthesis of1-(4-amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 400 mg of the mixed solution (1:1) of 4N hydrochloric acid and aceticacid was added 35 mg of ethyl1-(4-amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux with stirring for 3 hours andallowed to cool. The precipitate was collected by filtration, and washedwith distilled water, ethanol and diisopropylether successively toobtain 31 mg of the title compound as a pale yellow powder.

Melting point: 280° C. or higher

¹ HNMR (d₆ -DMSO) δ;

6.86 (brs, 2H), 7.00 (d, J=7 Hz, 1H), 8.12 (d, J=3 Hz, 1H), 8.39 (t, J=9Hz, 1H), 8.74 (s, 1H)

EXAMPLE 55

Synthesis of7-(3-aminoazetidin-1-yl)-1-(4-amino-5-fluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 110 mg of N,N-dimethylformamide were added 23 mg of1-(4-amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 20 mg of 3-aminoazetidine dihydrochloride, and 50 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 20minutes. After adding 500 mg of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 23 mg of the titlecompound as a colorless powder.

Melting point: 280° C. or higher

¹ HNMR (d₆ -DMSO) δ;

3.75 (m, 1H), 4.10 (m, 2H), 4.66 (m, 2H), 6.77 (brs, 2H), 6.92 (d, J=7Hz, 1H), 7.86 (d, J=14 Hz, 1H), 8.08 (d, J=3 Hz, 1H), 8.57 (s, 1H)

REFERENCE EXAMPLE 39

Synthesis of methyl 2,6-dichloro-5-fluoronicotinate

To 60 ml of dichloromethane were added 21.0 g of2,6-dichloro-5-fluoronicotinic acid, 10 ml of oxalylchloride, and 10drops of N,N-dimethylformamide, and the mixture was stirred at roomtemperature for one day. The solvent and the excess reagents weredistilled off under reduced pressure, and the residue was dissolved in50 ml of chloroform. 10 ml of methanol was added dropwise to thesolution, and the solution was stirred at room temperature for 60minutes, and 15 g of anhydrous potassium carbonate was added to thesolution and the solution was stirred for another 30 minutes. Thesolution was separated by adding 150 ml of chloroform and 150 ml ofdistilled water, and the chloroform layer was dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to obtain26.6 g of the title compound as a colorless crude oily residue.

REFERENCE EXAMPLE 40

Synthesis of methyl 6-t-butylamino-2,5-difluoronicotinate

To 30 ml of dimethylsulfoxide were added three quarter (19.95 g) of themethyl 2,6-dichloro-5-fluoronicotinate synthesized as described above,14.5 g of potassium fluoride (spray dried), and 1.6 g oftetramethylammonium chloride, and the mixture was stirred at 110° C. for2 and half hours and allowed to cool. After adding 100 ml of chloroform,the mixture was washed twice with 1 liter of distilled water, and oncewith 1 liter of 1% aqueous solution of sodium carbonate. The chloroformlayer was dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. Crude methyl 2,5,6-trifluoronicotinate was obtained inthe form of brown oily residue, and this residue was dissolved in 60 mlof acetonitrile, and 12.0 g of t-butylamine was added to this solution.The solution was concentrated under reduced pressure, and the residuewas separated by adding 100 ml of chloroform and 60 ml of distilledwater. The chloroform layer was dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The precipitate was dispersedin n-hexane, and collected by filtration to obtain 6.85 g of the titlecompound as a colorless crystals.

¹ HNMR (CDCl₃) δ;

1.50 (s, 9H), 3.86 (s, 3H), 5.04 (brs, 1H), 7.71 (dd, J=7 Hz, 11 Hz, 1H)

REFERENCE EXAMPLE 41

Synthesis of methyl6-t-butylamino-5-fluoro-2-(1,1,3,3-tetramethylbutylamino)nicotinate

To 7 ml N-methylpyrrolidone were added 2.44 g of methyl6-t-butylamino-2,5-difluoronicotinate and 4.0 g of1,1,3,3-tetramethylbutylamine, and the mixture was stirred at 140° C.for 16 hours and allowed to cool. After adding 50 ml of chloroform, themixture was washed three times with 300 ml of distilled water. Thechloroform layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The brown oily residue wassubjected to column chromatography (silica gel, 40 g;eluent:chloroform:n-hexane, 1:1) to obtain 2.90 g of the title compoundas a colorless oily residue.

¹ HNMR (CDCl₃) δ;

0.96 (s, 9H), 1.51 (s, 9H), 1.53 (s, 6H), 3.76 (s, 3H), 4.87 (brs, 1H),7.52 (d, J=12 Hz, 1H), 8.38 (brs, 1H)

REFERENCE EXAMPLE 42

Synthesis of2-t-butylamino-3-fluoro-5-methyl-6-(1,1,3,3-tetramethylbutylamino)pyridine

To 20 ml of tetrahydrofran was dispersed 850 mg of lithium aluminumhydride. The dispersion was water cooled and stirred simultaneously withthe dropwise addition of 2.80 g of methyl6-t-butylamino-5-fluoro-2-(1,1,3,3-tetramethylbut ylamino)nicotinatedissolved in 30 ml of tetrahydrofuran. The reactor was placed in an oilbath of 50° C., and the mixture was stirred for two and half hours. Thereactor was then water cooled and 8 ml of ethyl acetate was addeddropwise, and the mixture was stirred for 1 hour. 8 ml of ethanol wasadded dropwise, and the mixture was stirred for 1 hour, then 8 ml ofdistilled water was added dropwise, and the mixture was stirredovernight. The precipitate was separated by filtration, and the filtratewas concentrated under reduced pressure. The residue was subjected tocolumn chromatography (silica gel, 40 g; eluent: chloroform:n-hexane,1:1) to obtain 1.67 g of the title compound as a colorless oily residue.

¹ HNMR (CDCl₃) δ;

0.99 (s, 9H), 1.47 (s, 9H), 1.52 (s, 6H), 1.91 (s, 3H), 3.73 (brs, 1H),4.11 (brs, 1H), 6.81 (d, J=12 Hz, 1H)

REFERENCE EXAMPLE 43

Synthesis of 2,6-diamino-3-fluoro-5-methylpyridine

To 800 mg of trifluoroacetic acid was added 340 mg of2-t-butylamino-3-fluoro-5-methyl-6-(1,1,3,3-tetramethylbutylamino)pyridine,and the mixture was allowed to stand at room temperature for 30 minutes.The solution was concentrated under reduced pressure to obtain crude2,6-diamino-3-fluoro-5-methylpyridine as a pale brown solid residue.

EXAMPLE 56

Synthesis of ethyl1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 1 ml chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 280mg of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded all of 2,6-diamino-3-fluoro-5-methylpyridine as described abovetogether with 2 ml of methanol and 4 ml of chloroform. After allowing tostand at room temperature for 40 minutes, the solution was concentratedunder reduced pressure. To the residue were added 600 mg of anhydrouspotassium carbonate and 1 ml of N,N-dimethylformamide, and the mixturewas stirred at 85° C. for 15 minutes and allowed to cool. The solutionwas separated by adding 30 ml of chloroform and 300 ml of distilledwater, and the chloroform layer was washed twice with 300 ml ofdistilled water. The chloroform layer was dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. To the residue wasadded 0.5 ml of ethanol, and the mixture was allowed to stand overnight.The precipitate was dispersed in ethanol, collected by filtration, andwashed with ethanol and diisopropylether successively to obtain 171 mgof the title compound as a colorless powder.

Melting point: 198 to 202° C.

¹ HNMR (CDCl₃) δ;

1.40 (t, J=7 Hz, 3H), 2.02 (s, 3H), 4.39 (q, J=7 Hz, 2H), 4.71 (brs,2H), 7.25 (d, J=10 Hz, 1H), 8.34 (t, J=10 Hz, 1H), 8.34 (s, 1H)

EXAMPLE 57

Synthesis of1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 800 mg of the mixed solution (1:1) of 4N hydrochloric acid and aceticacid was added 160 mg of ethyl1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux with stirring for 30 minutes.After adding 0.5 ml of distilled water, the solution was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 145 mg of the titlecompound as a pale brown powder.

Melting point: 279 to 284° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

1.94 (s, 3H), 6.62 (brs, 2H), 7.57 (d, J=l1Hz, 1H), 8.40 (t, J=9 Hz,1H), 8.72 (s, 1H)

EXAMPLE 58

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 250 mg of N,N-dimethylformamide were added 80 mg of1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 60 mg of 3-aminoazetidine dihydrochloride, and 120 mg ofN-methylpyrrolidine, and the mixture was stirred at 85° C. for 45minutes. After adding 0.5 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 72 mg of the titlecompound as a colorless powder.

Melting point: 256 to 258° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

1.90 (s, 3H), 3.69 (m, 1H), 4.03 (m, 2H), 4.66 (m, 2H), 6.57 (brs, 2H),7.52 (d, J=l1Hz, 1H), 7.87 (d, J=14 Hz, 1H), 8.47 (s, 1H)

EXAMPLE 59

Synthesis of7-[3-(methylamino)azetidin-1-yl]-1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 90 mg of N,N-dimethylformamide were added 25 mg of1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 25 mg of 3-(methylamino)azetidine dihydrochloride, and 70 mg ofN-methylpyrrolidine, and the mixture was stirred at 85° C. for 45minutes. After adding 0.2 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 20 mg of the titlecompound as a colorless powder.

Melting point: 251 to 253° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

1.90 (s, 3H), 2.20 (s, 1H), 3.44 (m, 1H), 4.12 (m, 2H), 4.63 (m, 2H),6.57 (brs, 2H), 7.52 (d, J=11 Hz, 1H), 7.86 (d, J=14 Hz, 1H), 8.47 (s,1H)

REFERENCE EXAMPLE 44

Synthesis of 6-t-butylamino-2-chloro-3-cyano-5-fluoropyridine

To a solution of 7.6 g of 2,6-dichloro-3-cyano-5-fluoropyridine in 40 mlacetonitrile was added 8.8 g of t-butylamine, and the mixture wasstirred overnight at room temperature. The solvent was distilled off thereaction solution. The residue was separated by adding methylenechloride and water. The organic layer was dried over magnesium sulfate,and the solvent was distilled off to obtain 6 g of the title compound asa pale yellow powder.

Melting point: 84 to 85° C.

¹ HNMR (CDCl₃) δ;

1.50 (s, 9H), 5.15 (brs, 1H), 7.25 (d, J=l1Hz, 1H)

REFERENCE EXAMPLE 45

Synthesis of 2-benzylamino-6-t-butylamino-3-cyano-5-fluoropyridine

To 40 ml of N-methylpyrrolidone solution of 6 g6-t-butylamino-2-chloro-3-cyano-5-fluoropyridine was added 6.3 g ofbenzylamine, and the mixture was stirred under nitrogen atmosphere at160° C. for 3 hours and allowed to cool. The reaction solution wasseparated by adding chloroform and water, and the organic layer wasdried over magnesium sulfate, and the solvent was distilled off. Theprecipitated crystals were collected from the residue by filtration toobtain 2 g of the title compound as a pale yellow powder.

Melting point: 138 to 140° C.

¹ HNMR (CDCl₃) δ;

1.38 (s, 9H), 4.63 (d, J=6 Hz, 2H), 4.87 (brs, 1H), 5.25 (brs, 1H), 7.31(s, 5H)

REFERENCE EXAMPLE 46

Synthesis of 2-amino-6-t-butylamino-3-cyano-5-fluoropyridine

To 500 mg of 2-benzylamino-6-t-butylamino-3-cyano-5-fluoropyridine wereadded 3 ml acetic acid and 0.5 ml ethanol, and then, 10 microspatulas ofpalladium black, and the mixture was stirred under hydrogen atmosphereat 60° C. for 2 days. The catalyst was removed with a membrane filter,and the solvent of the filtrate was distilled off. To the residue wasadded chloroform, and the mixture was washed with aqueous solution ofsodium hydrogencarbonate. The organic layer was collected, dried overmagnesium sulfate. The solvent was distilled off to obtain 300 mg of thetitle compound.

EXAMPLE 60

Synthesis of ethyl1-(6-t-butylamino-3-cyano-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinolone-3-carboxylate

A solution of 300 mg of unpurified2-amino-6-t-butylamino-3-cyano-5-fluoropyridine in 2 ml ethanol wasadded dropwise to a solution of 420 mg of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate in 2 ml ethanol atroom temperature, and the mixture was stirred overnight. The solvent wasdistilled off the reaction solution, and to the residue were added 3 mlof N,N-dimethylformamide and 210 mg of potassium carbonate, and themixture was stirred at room temperature for 90 minutes and 80° C. for 2hours. The reaction solution was extracted by adding water and ethylacetate, and the organic layer was collected and dried over magnesiumsulfate. The solvent was distilled off, and the residue was collected byfiltration using ethanol and washed with diethylether to obtain 280 mgof the title compound as a pale yellow powder.

Melting point: 245° C. or higher (decomposed)

¹ HNMR (CDCl₃) δ;

1.39 (s, 9H), 1.41 (t, J=7 Hz, 3H), 4.41 (q, J=7 Hz, 2H), 5.39 (brs,1H), 7.43 (d, J=10 Hz, 1H), 8.32 (t, J=9 Hz, 1H), 8.53 (s, 1H)

EXAMPLE 61

Synthesis of1-(6-amino-3-cyano-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinolone-3-carboxylicacid

To 280 mg of ethyl1-(6-t-butylamino-3-cyano-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinolone-3-carboxylatewas added 3 ml of 12N hydrochloric acid, and the mixture was heatedunder reflux for 6 hours and allowed to cool. The solid precipitate wascollected by filtration and washed with ethanol and diethylethersuccessively to obtain 120 mg of the title compound as a pale yellowpowder.

Melting point: 277° C. or higher (decomposed)

¹ HNMR (d₆ -DMSO) 8;

8.00 (brs, 2H), 8.21 (d, J=l1Hz, 1H), 8.40 (t, J=9 Hz, 1H), 9.05 (s, 1H)

EXAMPLE 62

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-3-cyano-5-fluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-4-oxoquinolone-3-carboxylicacid

A solution in 300 mg of N,N-dimethylformamide of 40 mg of3-aminoazetidine dihydrochloride and 80 mg of triethylamine was stirredat 90° C., and 50 mg of1-(6-amino-3-cyano-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinolone-3-carboxylicacid was added to the solution, and stirred at 90° C. for 10 minutes. Tothe reaction solution was added 1 ml of ethanol, and the solidprecipitate was collected and dried to obtain 36 mg of the titlecompound as a pale yellow powder.

Melting point: 290° C. or higher

¹ HNMR (d₆ -DMSO) δ;

4.09 (m, 1H), 4.48 (m, 2H), 4.79 (m, 2H), 7.90-8.06 (m, 3H), 8.16 (d,J=l1Hz, 1H), 8.33 (brs, 2H), 8.85 (s, 1H)

EXAMPLE 63

Synthesis of ethyl1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate

To 3.4 g of ethyl 2,4,5-trifluoro-3-methylbenzoylacetate was added 3.2 gof acetic anhydride and 2.3 g of triethyl orthoformate, and the mixturewas heated under reflux for 4 hours, and the solvent was distilled off.Toluene was added to the residue, and the solution was azeotropicallydistilled. After adding 5 ml of ethanol to the residue, a solution of2.7 g of 2-amino-6-(t-butylamino)-3,5-difluoropyridine in 20 ml ethanolwas added dropwise at 0° C., and the mixture was stirred at roomtemperature for 20 minutes. The solvent was distilled off the reactionsolution, and the residue was subjected to silica gel columnchromatography, and from the eluent of ethyl acetate: hexane, 1:8 wasobtained 4.6 g of ethyl2-(2,4,5-trifluoro-3-methylbenzoyl)-3-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]aminoacrylateas an oil.

To the solution of 4.6 g of the thus obtained ethyl2-(2,4,5-trifluoro-3-methylbenzoyl)-3-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]aminoacrylatein 10 ml dimethylformamide was added 1.35 g of potassium carbonate, andthe mixture was stirred at 100° C. for 50 minutes. The reaction solutionwas extracted by adding water and acetic acid, and the organic layer wascollected and dried over magnesium sulfate. The solvent was distilledoff, and the residue was collected by filtration with ethanol and washedwith diethylether to obtain 2.6 g of the title compound as a pale yellowpowder.

Melting point: 207 to 211° C.

¹ HNMR (CDCl₃) δ;

1.34-1.48 (m, 12H), 1.82 (d, J=3 Hz, 3H), 4.40 (q, J=7 Hz, 2H), 4.75(brs, 1H), 7.23 (t, J=9 Hz, 1H), 8.22 (t, J=10 Hz, 1H), 8.50 (s, 1H)

EXAMPLE 64

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoguinoline-3-carboxylicacid

To 2.5 g of ethyl1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylatewas added 10 ml of 12N hydrochloric acid, and the mixture was heatedovernight under reflux. The reaction solution was allowed to stand, andthe solid precipitate was collected by filtration and washed withethanol and then, with diethylether to obtain 1.7 g of the titlecompound as a pale yellow powder.

Melting point: 274 to 277° C.

¹ HNMR (d₆ -DMSO) δ;

1.84 (s, 3H), 6.91 (brs, 2H), 8.03 (t, J=9 Hz, 1H), 8.25 (t, J=9 Hz,1H), 8.93 (s, 1H)

EXAMPLE 65

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoguinoline-3-carboxylicacid

A solution of 70 mg of 3-aminoazetidine dihydrochloride, 200 mg of1,8-diazabicyclo[5,4,0]undecene, and 300 mg of pyridine was stirred at100° C., and 110 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid was added to the solution and the solution was stirred at 100° C.for 6 minutes. The solvent was distilled off the reaction solution, andto the residue was added one drop of acetic acid and 3 ml of ethanolwith heating, and the solution was allowed to stand. The solidprecipitate was collected and dried to obtain 13 mg of the titlecompound as a pale yellow powder.

Melting point: 280° C. or higher

¹ HNMR (d₆ -DMSO) δ;

1.60 (s, 3H), 3.77 (m, 2H), 3.93 (m, 1H), 4.46 (m, 2H), 6.86 (brs, 2H),7.75 (d, J=13 Hz, 1H), 7.95 (t, J=9 Hz, 1H), 8.70 (s, 1H)

EXAMPLE 66

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-8-methyl-7-(3-methylaminoazetidin-1-yl)-1, 4-dihydro-4-oxoquinolone-3-carboxylic acid

The title compound (20 mg) was obtained as a pale yellow powder in asimilar manner to Example 65 except that 180 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 110 mg of 3-aminoazetidine dihydrochloride were used.

Melting point: 229° C. or higher

¹ HNMR (d₆ -DMSO) δ;

1.63 (s, 3H), 2.21 (s, 3H), 3.87 (m, 1H), 4.02 (m, 1H), 4.43 (m, 2H),6.86 (brs, 2H), 7.75 (d, J=14 Hz, 1H), 7.97 (t, J=10 Hz, 1H), 8.71 (s,1H)

EXAMPLE 67

Synthesis of7-(3-amino-3-methylazetidin-1-yl)-1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinolone-3-carboxylicacid

The title compound (60 mg) was obtained as a pale yellow powder in asimilar manner to Example 65 except that 180 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 110 mg of 3-amino-3-methylazetidine dihydrochloride were used.

Melting point: 235° C. or higher

¹ HNMR (d₆ -DMSO) δ;

1.37 (s, 3H), 1.62 (s, 3H), 3.87 (m, 1H), 4.08 (m, 3H), 6.85 (brs, 2H),7.74 (d, J=14 Hz, 1H), 7.96 (t, J=10 Hz, 1H), 8.70 (s, 1H)

EXAMPLE 68

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-6,8-difluoro-7-(3-methylaminoazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 200 mg of N,N-dimethylformamide were added 65 mg1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 45 mg of 3-methylaminoazetidine dihydrochloride, and 100 mg ofN-methylpyrrolidine together with 3 drops of ethanol, and the mixturewas stirred at 85° C. for 30 minutes. After adding 0.2 ml of ethanol,the solution was allowed to cool, and the precipitate was collected byfiltration and washed with ethanol and diisopropylether successively toobtain 52 mg of the title compound as a colorless powder.

Melting point: 262 to 268° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

2.19 (s, 3H), 3.52 (m, 1H), 4.01 (m, 2H), 4.44 (m, 2H), 6.75 (brs, 2H),7.77 (d, J=13 Hz, 1H), 7.99 (t, J=9 Hz, 1H), 8.74 (s, 1H)

EXAMPLE 69

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 270 mg of N,N-dimethylformamide were added 110 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 50 mg of 3-hydroxyazetidine hydrochloride, and 100 mg ofN-methylpyrrolidine together with 3 drops of ethanol, and the mixturewas stirred at 85° C. for 25 minutes. After adding 0.5 ml of ethanol,the solution was allowed to cool, and the precipitate was collected byfiltration and washed with ethanol and diisopropylether successively toobtain 101 mg of the title compound as a pale yellow powder.

Melting point: 215 to 220° C.

¹ HNMR (d₆ -DMSO) δ;

4.06 (m, 2H), 4.51 (m, 3H), 5.75 (brs, 1H), 6.76 (brs, 2H), 7.79 (d,J=13 Hz, 1H), 7.99 (t, J=9 Hz, 1H), 8.75 (s, 1H)

EXAMPLE 70

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 3.5 g of N,N-dimethylformamide were added 2.00 g of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 1.00 g of 3-hydroxyazetidine hydrochloride, and 2.00 g ofN-methylpyrrolidine together with 0.2 ml of ethanol, and the mixture wasstirred at 85° C. for 10 minutes. The solvent and the like weredistilled off under reduced pressure. After adding 10 ml of ethanol tothe residue, the mixture was heated under reflux for 10 minutes andallowed to cool, and the precipitate was collected by filtration andwashed with ethanol and diisopropylether successively to obtain 2.10 gof the title compound as a pale yellow powder.

Melting point: 235 to 238° C.

¹ HNMR (d₆ -DMSO) δ;

4.18 (m, 2H), 4.48 (m, 1H), 4.72 (m, 2H), 5.74 (d, J=6 Hz, 1H), 6.76(brs, 2H), 7.86 (d, J=14 Hz, 1H), 7.95 (t, J=9 Hz, 1H), 8.70 (s, 1H)

EXAMPLE 71

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-6,8-difluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 280 mg of N,N-dimethylformamide were added 125 mg1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 60 mg of 3-hydroxyazetidine hydrochloride, and 120 mg ofN-methylpyrrolidine together with 3 drops of ethanol, and the mixturewas stirred at 85° C. for 10 minutes. After adding 0.8 ml of ethanol,the solution was allowed to cool, and the precipitate was collected byfiltration and washed with ethanol and diisopropylether successively toobtain 90 mg of the title compound as a pale yellow powder.

Melting point: 269 to 272° C.

¹ HNMR (d₆ -DMSO) δ;

4.06 (m, 2H), 4.51 (m, 3H), 5.75 (brs, 1H), 6.76 (brs, 2H), 7.79 (d,J=13 Hz, 1H), 7.99 (t, J=9 Hz, 1H), 8.75 (s, 1H)

EXAMPLE 72

Synthesis of ethyl8-bromo-1-[6-(t-butylamino)-5-fluoropyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 1 ml of chloroform solution of ethyl3-ethoxy-2-(3-bromo-2,4,5-trifluorobenzoyl)acrylate prepared from 0.65 gof ethyl 3-bromo-2,4,5-trifluorobenzoylacetate by normal process wasadded 0.3 g of 2-amino-6-(t-butylamino)-5-fluoropyridine. The solutionwas concentrated under reduced pressure to obtain yellowish orange solidresidue. To this residue were added 0.4 g of anhydrous potassiumcarbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirredat 90° C. for 25 minutes and allowed to cool. The solution was separatedby adding 25 ml of chloroform and 400 ml of distilled water, and thechloroform layer was washed with 400 ml of distilled water, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.After adding 2 ml of ethanol, the solution was and allowed to stand. Theprecipitate was dispersed in ethanol and collected by filtration, andwashed with ethanol and diisopropylether successively to obtain 0.53 gof the title compound as a pale yellow powder.

Melting point: 192 to 195° C.

¹ HNMR (CDCl₃) δ;

1.37 (s, 9H), 1.40 (t, J=7 Hz, 3H), 4.40 (q, J=7 Hz, 2H), 4.83 (brs,1H), 6.50 (dd, J=3 Hz, 8 Hz, 1H), 7.24 (dd, J=8 Hz, 10 Hz, 1H), 8.35 (t,J=9 Hz, 1H), 8.65 (s, 1H)

EXAMPLE 73

Synthesis of1-(6-amino-5-fluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 4 ml of the mixed solution (1:1) of 4N hydrochloric acid and aceticacid was added 480 mg of ethyl8-bromo-1-[6-(t-butylamino)-5-fluoropyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux with stirring for 2 hours. Afteradding 4 ml of distilled water, the solution was allowed to cool, andthe precipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 345 mg of the title compound asa colorless powder.

Melting point: 245 to 251° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

6.84-6.92 (m, 3H), 7.64 (dd, J=8 Hz, 11 Hz,1H), 8.40 (t, J=9 Hz, 1H),8.79 (s, 1H)

EXAMPLE 74

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-5-fluoropyridin-2-yl)-8-bromo-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 250 mg of N,N-dimethylformamide were added 80 mg of1-(6-amino-5-fluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 55 mg of 3-aminoazetidine dihydrochloride, and 150 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 10minutes. After adding 0.3 ml of ethanol, the solution was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 68 mg of the titlecompound as a colorless powder.

Melting point: 245 to 250° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.72 (m, 1H), 4.02 (m, 2H), 4.67 (m, 2H), 6.73 (dd, J=2 Hz, 8 Hz, l),6.82 (brs, 2H), 7.59 (dd, J=8 Hz, 10 Hz, 1H), 7.87 (d, J=14 Hz, 1H),8.69 (s, 1H)

EXAMPLE 75

Synthesis of1-(6-amino-5-fluoropyridin-2-yl)-8-bromo-6-fluoro-7-(3-methylaminoazetidin-1-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 250 mg of N,N-dimethylformamide were added 80 mg of1-(6-amino-5-fluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 80 mg of 3-methylaminoazetidine dihydrochloride, and 200 mg ofN-methylpyrrolidine, and the mixture was stirred at 85° C. for 10minutes. After adding 0.5 ml of ethanol, the solution was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 66 mg of the titlecompound as a colorless powder.

Melting point: 210 to 218° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

2.22 (s, 3H), 3.48 (m, 1H), 4.12 (m, 2H), 4.61 (m, 2H), 6.74 (d, J=10Hz, 2H), 6.81 (brs, 2H), 7.59 (t, J=10 Hz, 1H), 7.87 (d, J=14 Hz, 1H),8.68 (s, 1H)

REFERENCE EXAMPLE 47

Synthesis of 2-amino-5-chloro-3,6-difluoropyridine

To 25 ml of methanol were added 2.7 g of2-amino-4-bromo-5-chloro-3,6-difluoropyridine and 1.15 g oftriethylamine together with 0.145 g of 10% palladium on carbon, and themixture was hydrogenated at room temperature for 1.5 hours. The catalystwas separated by filtration, and the solvent and the like were distilledoff under reduced pressure. To the residue was added 50 ml ofchloroform, and the mixture was washed with 30 ml of distilled water.The chloroform layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting colorless flakecrystals were dispersed in a mixed solution of diisopropylether andn-hexane (1:2), and collected by filtration to obtain 1.62 g of thetitle compound.

REFERENCE EXAMPLE 48

Synthesis of 2-amino-5-chloro-3-fluoro-6-(p-methoxybenzylamino)pyridine

To 2 ml of N-methylpyrrolidone was added 510 mg of2-amino-5-chloro-3,6-difluoropyridine and 910 mg ofp-methoxybenzylamine, and the mixture was stirred at 150° C. for oneday, and allowed to cool. After adding a mixed solution of 60 ml benzeneand n-hexane (1:1, v/v), the solution was washed twice with 400 ml ofdistilled water. The organic layer was dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure to obtain 960 mg of thetitle compound as a brown crude oil.

¹ HNMR (CDCl₃) δ;

3.80 (s, 3H), 4.35 (brs, 2H), 4.50 (m, 2H), 4.86 (brs, l), 6.87 (d, J=8Hz, 2H), 7.15 (d, J=10 Hz, 1H), 7.27 (d, J=8 Hz, 2H)

EXAMPLE 76

Synthesis of ethyl8-chloro-1-[5-chloro-3-fluoro-6-(p-methoxybenzylamino)pyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 2 ml chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.56g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 0.66 g of2-amino-5-chloro-3-fluoro-6-(p-methoxybenzylamino)pyridine. The solutionwas concentrated under reduced pressure. To the residue were added 0.5 gof anhydrous potassium carbonate and 1.5 ml of N,N-dimethylformamide,and the mixture was stirred at 90° C. for 20 minutes and allowed tocool. The solution was separated by adding 30 ml of chloroform and 300ml of distilled water, and the chloroform layer was washed with 300 mlof distilled water, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The solution was allowed to standafter adding 4 ml of ethanol. The precipitate was collected byfiltration, washed with ethanol and diisopropylether successively toobtain 0.56 g of the title compound as a pale yellow powder.

Melting point: 168 to 171° C.

¹ HNMR (CDCl₃) δ;

1.40 (t, J=7 Hz, 3H), 3.80 (s, 3H), 4.40 (d, J=7 Hz, 2H), 4.42 (q, J=7Hz, 2H), 5.46 (brs, 1H), 6.83 (d, J=9 Hz, 2H), 7.18 (d, J=9 Hz, 2H),7.53 (d, J=8 Hz, 1H), 8.29 (t, J=9 Hz, 1H), 8.48 (s, 1H)

EXAMPLE 77

Synthesis of ethyl1-(6-amino-5-chloro-3-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 530 mg of ethyl8-chloro-1-[5-chloro-3-fluoro-6-(p-methoxybenzylamino)pyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylatewas added 2 ml of trifluoro acetate, and the solution was allowed tostand for 30 minutes at room temperature. The solution was concentratedunder reduced pressure, and 4 ml of ethanol was added to the residue,and the solution was concentrated under reduced pressure. Theprecipitate was dispersed in ethanol, collected by filtration, washedwith ethanol and diisopropylether successively to obtain 462 mg of thetitle compound as a pale yellow powder.

Melting point: 186 to 189° C.

¹ HNMR (CDCl₃) δ;

1.40 (t, J=7 Hz, 3H), 4.40 (q, J=7 Hz, 2H), 5.02 (brs, 2H), 7.57 (d, J=8Hz, 2H), 8.30 (t, J=9 Hz, 1H), 8.48 (s, 1H)

EXAMPLE 78

Synthesis of1-(6-amino-5-chloro-3-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 2 ml of the mixed solution of 4N hydrochloric acid and acetic acid(1:1) was added 430 mg of ethyl1-(6-amino-5-chloro-3-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux for 6 hours with stirring andallowed to cool. The precipitate was collected by filtration, and washedwith ethanol and diisopropylether successively to obtain 375 mg of thetitle compound as a colorless powder.

Melting point: 280° C. or higher

¹ HNMR (d₆ -DMSO) δ;

6.86 (brs, 2H), 8.15 (d, J=9 Hz, 1H), 8.38 (t, J=9 Hz, 1H), 8.95 (s, 1H)

EXAMPLE 79

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-5-chloro-3-fluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 280 mg of N,N-dimethylformamide were added 90 mg of1-(6-amino-5-chloro-3-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 70 mg of 3-aminoazetidine dihydrochloride, and 160 mg ofN-methylpyrrolidine, and the mixture was stirred at 85° C. for 20minutes. After adding 0.3 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 50 mg of the titlecompound as a colorless powder.

Melting point: 240 to 245° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.71 (m, 1), 4.06 (m, 2H), 4.66 (m, 2H), 6.79 (brs, 2H), 7.85 (d, J=14Hz, 1H), 8.08 (d, J=9HZ, 1H), 8.70 (s, 1H)

REFERENCE EXAMPLE 49

Synthesis of 2,3,5-trifluoro-6-isopropylaminopyridine

To 20 ml of acetonitrile were added 6.0 g of 2,3,5,6-tetrafluoropyridineand 6.0 g of isopropylamine, and the mixture was stirred at roomtemperature for 2 hours and concentrated under reduced pressure. Afteradding 40 ml of chloroform, the solution was washed with 50 ml of 3%aqueous solution of potassium carbonate. The chloroform layer was driedover anhydrous magnesium sulfate and concentrated under reduced pressureto obtain 1.9 g of the title compound as a colorless oil.

REFERENCE EXAMPLE 50

Synthesis of3,5-difluoro-2-isopropylamino-6-(p-methoxybenzylamino)pyridine

To 4.1 g of N-methylpyrrolidone were added all amount of the2,3,5-trifluoro-6-isopropylaminopyridine as described above togetherwith 3.1 g of p-methoxybenzylamine, and the mixture was stirred at 150°C. for 15 hours and allowed to cool. After adding 50 ml of the mixedsolution of benzene and n-hexane (1:1, v/v), the solution was washedtwice with 400 ml of distilled water. The organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toobtain 3.9 g of the title compound as a brown crude oil.

REFERENCE EXAMPLE 51

Synthesis of 2-amino-3,5-difluoro-6-isopropylaminopyridine

To 1.9 g of3,5-difluoro-2-isopropylamino-6-(p-methoxybenzylamino)pyridine was added4 ml of trifluoroacetate, and the mixture was allowed to stand at roomtemperature for 15 minutes. The solution was concentrated under reducedpressure, and 25 ml of chloroform was added to the residue, and thesolution was washed with 25 ml of 5% aqueous solution of sodiumcarbonate. The chloroform layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure, and the residue wassubjected to column chromatography (silica gel, 40 g; eluent:chloroform)to obtain 0.6 g of the title compound as a brown oil.

EXAMPLE 80

Synthesis of ethyl8-chloro-6,7-difluoro-1-(3,5-difluoro-6-isopropylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 2.5 ml of chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.70g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 600 mg of 2-amino-3,5-difluoro-6-isopropylaminopyridine. Thesolution was concentrated under reduced pressure. To the residue wereadded 600 mg of anhydrous potassium carbonate and 2 ml ofN,N-dimethylformamide, and the mixture was stirred at 90° C. for 20minutes and allowed to cool. The solution was separated by adding 30 mlof chloroform and 400 ml of distilled water, and the chloroform layerwas washed twice with 400 ml of distilled water, dried over anhydrousmagnesium sulfate, concentrated under reduced pressure, and allowed tostand. The precipitate was collected by filtration, washed with ethanoland diisopropylether successively to obtain 620 mg of the title compoundas a pale yellow powder.

Melting point: 206 to 209° C.

¹ HNMR (CDCl₃) δ;

1.20 (d, J=7 Hz, 3H), 1.24 (d, J=7 Hz, 3H), 1.40 (t, J=7 Hz, 3H), 4.11(m, 1H), 4.40 (q, J=7 Hz, 2H), 4.60 (brs, 1H), 7.22 (dd, J=8 Hz, 9 Hz,1H), 8.32 (dd, J=8 Hz, 10 Hz, 1H), 8.49 (s, 1H)

EXAMPLE 81

Synthesis of8-chloro-6,7-difluoro-1-(3,5-difluoro-6-isopropylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 3 ml of the mixed solution of 4N hydrochloric acid and acetic acid(1:1, v/v) was added 300 mg of ethyl8-chloro-6,7-difluoro-1-(3,5-difluoro-6-isopropylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux for 19 hours with stirring. Theprecipitate was collected by filtration, washed with ethanol anddiisopropylether successively to obtain 265 mg of the title compound asa yellow powder.

Melting point: 226 to 230° C.

¹ HNMR (d₆ -DMSO) δ;

1.10 (d, J=7 Hz, 3H), 1.16 (d, J=7 Hz, 3H), 3.94 (m, 1H), 7.02 (brd, J=8Hz, 2H), 7.97 (t, J=9 Hz, 1H), 8.39 (t, J=9 Hz, 1H), 8.92 (s, 1H)

EXAMPLE 82

Synthesis of7-(3-aminoazetidin-1-yl)-8-chloro-6-fluoro-1-(3,5-difluoro-6-isopropylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 160 mg of N,N-dimethylformamide were added 55 mg of8-chloro-6,7-difluoro-1-(3,5-difluoro-6-isopropylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 35 mg of 3-aminoazetidine dihydrochloride, and 120 mg ofN-methylpyrrolidine, and the mixture was stirred at 80° C. for 30minutes. After adding 0.5 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 51 mg of the titlecompound as a colorless powder.

Melting point: 220 to 223° C.

¹ HNMR (d₆ -DMSO) δ;

1.13 (d, J=7 Hz, 3H), 1.16 (d, J=7 Hz, 3H), 3.70 (m, 1H), 3.96 (m, 2H),4.06 (m, 1H), 4.65 (m, 2H), 6.92 (brd, J=7 Hz, 2H), 7.87 (d, J=14 Hz,1H), 7.92 (t, J=9 Hz, 1H), 8.66 (s, 1H)

EXAMPLE 83

Synthesis of ethyl 1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridin-2-yl]-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 20 ml of chloroform solution of ethyl3-ethoxy-2-pentafluorobenzoylacrylate prepared from 5.6 g of ethyl2,3,4,5,6-pentafluorobenzoylacetate by normal process was added2-amino-3,5-difluoro-6-(p-methoxybenzylamino)pyridine until thedisappearance of the ethyl acrylate spot in TLC analysis. The solutionwas concentrated under reduced pressure. To the residue were added 4.3 gof anhydrous potassium carbonate and 15 ml of N,N-dimethylformamide, andthe mixture was stirred at 90° C. for 15 minutes and allowed to cool.The solution was separated by adding 100 ml of chloroform and 1 liter ofdistilled water, and the chloroform layer was washed twice with 1 literof distilled water, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The precipitate was dispersed inethanol, collected by filtration, and washed with ethanol anddiisopropylether successively to obtain 6.15 g of the title compound asa colorless powder.

Melting point: 203 to 208° C.

¹ HNMR (CDCl₃) δ;

1.40 (t, J=7 Hz, 3H), 3.80 (s, 3H), 4.40 (d, J=7 Hz, 2H), 4.42 (q, J=7Hz, 2H), 5.46 (brs, IH), 6.83 (d, J=9 Hz, 2H), 7.18 (d, J=9 Hz, 2H),7.53 (d, J=8 Hz, 1H), 8.29 (t, J=9 Hz, 1H), 8.48 (s, 1H)

EXAMPLE 84

Synthesis of ethyl1-(6-amino-3,5-difluoropyridin-2-yl)-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 1080 mg of ethyl1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridin-2-yl]-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylatewas added 4 ml of trifluoroacetic acid, and the mixture was allowed tostand at room temperature for 30 minutes. The solution was concentratedunder reduced pressure, and 4 ml of ethanol was added to the residue,and the solution was again concentrated under reduced pressure. Theprecipitate was dispersed in ethanol, collected by filtration, andwashed with ethanol to obtain 960 mg of the title compound as a graypowder.

Melting point: 223 to 230° C.

¹ HNMR (CDCl₃) δ;

1.39 (t, J=7 Hz, 3H), 4.38 (d, J=7 Hz, 2H), 4.83 (brs, 2H), 6.83 (d, J=9Hz, 2H), 7.35 (t, J=9 Hz, 1H), 8.32 (s, 1H)

EXAMPLE 85

Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 2 ml of the mixed solution (1:1) of 4N hydrochloric acid and aceticacid was added 320 mg of ethyl1-(6-amino-3,5-difluoropyridin-2-yl)-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux for 3 hours with stirring, andallowed to cool. The precipitate was collected by filtration, and washedwith ethanol to obtain 280 mg of the title compound as a colorlesspowder.

Melting point: 236 to 242° C.

¹ HNMR (d₆ -DMSO) δ;

6.82 (brs, 2H), 8.03 (t, J=9 Hz, 1H), 8.92 (s, 1H)

EXAMPLE 86

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-3,5-difluoropyridin-2-yl)-5,6,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 300 mg of N,N-dimethylformamide were added 100 mg of1-(6-amino-3,5-difluoropyridin-2-yl)-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 30minutes. After adding 0.3 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 50 mg of the titlecompound as a pale yellow powder.

Melting point: 264 to 271° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.77 (m, 1H), 3.96 (m, 2H), 4.46 (m, 2H), 6.75 (brs, 2H), 7.97 (t, J=9Hz, 1H), 8.66 (s, 1H)

EXAMPLE 87

Synthesis of ethyl5-benzylamino-1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridin-2-yl]-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 8 ml of toluene were added 1.58 g of ethyl1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridin-2-yl]-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylatetogether with 0.68 g of benzylamine, and the mixture was stirred at 110°C. for 20 minutes and allowed to cool. After adding 15 ml of toluene and15 ml of n-hexane, the mixture was washed twice with 300 ml of distilledwater. The organic layer was dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. To the residue was added 4 ml ofethanol, and the solution was allowed to stand, and the precipitate wascollected by filtration and washed with ethanol to obtain 1.20 g of thetitle compound as a yellow powder.

Melting point: 146 to 148° C.

¹ HNMR (CDCl₃) δ;

1.37 (t, J=7 Hz, 3H), 3.79 (s, 3H), 4.37 (q, J=7 Hz, 2H), 4.47 (brs,1H), 4.68 (m, 2H), 5.01 (brs, 1H), 6.84 (d, J=9 Hz, 2H), 7.16-7.40 (m,10H), 8.22 (s, 1H)

EXAMPLE 88

Synthesis of ethyl1-(6-amino-3,5-difluoropyridin-2-yl)-5-benzylamino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 600 mg of ethyl5-benzylamino-1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridin-2-yl]-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylatewas added 2 ml of trifluoroacetic acid, and the mixture was allowed tostand at room temperature for 20 minutes. The solution was concentratedunder reduced pressure, and 3 ml of ethanol was added to the residue,and the solution was again concentrated under reduced pressure. Theprecipitate was dispersed in ethanol, collected by filtration and washedwith ethanol to obtain 530 mg of the title compound as a yellow powder.

Melting point: 176 to 180° C.

¹ HNMR (CDCl₃) δ;

1.36 (t, J=7 Hz, 3E), 4.36 (q, J=7 Hz, 2H), 4.47 (brs, 1H), 4.68 (d, J=4Hz, 2H), 4.74 (brs, 1H), 6.84 (d, J=9 Hz, 2H), 7.24-7.40 (m, 6H), 8.21(s, 1H)

EXAMPLE 89

Synthesis of ethyl5-amino-1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylateTo 5 ml of acetic acid was added 260 mg of ethyl1-(6-amino-3,5-difluoropyridin-2-yl)-5-benzylamino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylatetogether with 50 mg of 10% palladium on carbon, and the mixture washydrogenated at room temperature for 4 hours. The catalyst was separatedby filtration, and the solvent and the like were distilled off underreduced pressure. The procedure of adding 10 ml of ethanol to theresidue and concentrating under reduced pressure was repeated twice. Theprecipitate was dispersed in ethanol, collected by filtration, andwashed with ethanol and diisopropylether successively to obtain 160 mgof the title compound as a pale yellow powder.

Melting point: 225 to 230° C.

¹ HNMR (CDCl₃) δ;

1.38 (t, J=7 Hz, 3H), 4.38 (q, J=7 Hz, 2H), 4.73 (brs, 2H), 4.68 (d, J=4Hz, 2H), 6.8 (brs, 2H), 6.84 (d, J=9 Hz, 2H), 7.32 (t, J=9 Hz, l), 8.25(s, 1H)

EXAMPLE 90

Synthesis of5-amino-1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 1.5 ml of the mixed solution (1:1) of 4N hydrochloric acid and aceticacid was added 145 mg of ethyl5-amino-1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate,and the mixture was heated under reflux for 17 hours with stirring andallowed to cool. The precipitate was collected by filtration, and washedwith ethanol and to obtain 129 mg of the title compound as a yellowpowder.

¹ HNMR (d₆ -DMSO) δ;

6.78 (brs, 2H), 7.75 (brs, 1H), 7.99 (t, J=9 Hz, 1), 8.77 (s, 1H)

EXAMPLE 91

Synthesis of5-amino-7-(3-aminoazetidin-1-yl)-1-(6-amino-3,5-difluoropyridin-2-yl)-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 210 mg of N,N-dimethylformamide were added 50 mg of5-amino-1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 40 mg of 3-aminoazetidine dihydrochloride, and 150 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour,and concentrated under reduced pressure. The procedure of adding 2 ml ofdiisopropylether to the residue, stirring and decanting was repeatedtwice. 2 ml of ethanol and 40 mg of N-methylpyrrolidine were added tothe residue, and the mixture was allowed to stand overnight, and theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 26 mg of the title compound as apale yellow powder.

Melting point: 205 to 210° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.72 (m, 1H), 3.88 (m, 2H), 4.37 (m, 2H), 6.71 (brs, 2H), 7.23 (brs,2H), 7.94 (t, J=9 Hz, 1H), 8.50 (s, 1H)

EXAMPLE 92

Synthesis of ethyl1-(6-t-butylamino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 10 ml of chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluoro-6-nitrobenzoyl)acrylate preparedfrom 3.25 g of ethyl 3-chloro-2,4,5-trifluoro-6-nitrobenzoylacetate bynormal process was added 2.14 g of2-amino-3,5-difluoro-6-t-butylaminopyridine. The solution wasconcentrated under reduced pressure, and to the residue were added 2.7 gof anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide, andthe mixture was stirred at 90° C. for 5 minutes and allowed to cool. Thesolution was separated by adding 100 ml of chloroform and 500 ml of 2%aqueous solution of citric acid, and the chloroform layer was washedtwice with 500 ml of 2% aqueous solution of citric acid, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The precipitate was dispersed in ethanol, collected by filtration,washed with ethanol and diisopropylether successively to obtain 3.13 gof the title compound as a pale yellow powder.

Melting point: 215 to 217° C.

¹ HNMR (CDCl₃) δ;

1.37 (t, J=7 Hz, 3H), 1.39 (s, 9H), 4.39 (q, J=7 Hz, 2H), 4.77 (brs,1H), 7.24 (t, J=8 Hz, 1H), 8.35 (t, J=9 Hz, 1H), 8.52 (s, 1H)

EXAMPLE 93

Synthesis of5-amino-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 10 ml of formic acid was added 960 mg of ethyl1-(6-t-butylamino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylatetogether with 1.0 g of iron powder, and the mixture was stirred at 80 to90° C. for 5 hours and 40 minutes. The insoluble content was separatedby filtration through celite, and the content separated by the celiteand the celite were washed with formic acid and chloroform. The filtrateand the washings were concentrated under reduced pressure. To theresidue was added the 6 ml of the mixed solution of 4N hydrochloric acidand acetic acid (1:1), and the mixture was heated under reflux for 2hours with stirring and allowed to cool. The precipitate was collectedby filtration and washed with ethanol and diisopropylether successivelyto obtain 625 mg of the title compound as a yellow powder.

Melting point: 280° C. or higher

¹ HNMR (d₆ -DMSO) δ;

6.77 (brs, 2H), 7.94 (t, J=9 Hz, 1H), 8.20 (brs, 2H), 8.70 (s, 1H)

EXAMPLE 94

Synthesis of5-amino-7-(3-aminoazetidin-1-yl)-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 550 mg of pyridine were added 185 mg of 5-amino-1- (6-amino-3 ,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 110 mg of 3-aminoazetidine dihydrochloride, and 200 mg ofN-methylpyrrolidine, and the mixture was stirred at 100° C. for 30minutes, and concentrated under reduced pressure. After adding 2 ml ofethanol, the mixture was stirred, and the precipitate was collected byfiltration and washed with ethanol and diisopropylether successively toobtain 48 mg of the title compound as a yellow powder.

¹ HNMR (d₆ -DMSO) δ;

3.83 (m, 1H), 4.14 (m, 2H), 4.61 (m, 2H), 6.71 (brs, 2H), 7.52 (brs,2H), 7.89 (t, J=9 Hz, 1H), 8.51 (s, 1H)

EXAMPLE 95

Synthesis of ethyl6,7-difluoro-1-(3,5-difluoro-6-p-methoxybenzylaminopyridin-2-yl)-8-methyl-5-nitro-1,4-dihydro-4-oxoguinoline-3-carboxylate

To 5.0 g of ethyl 3,4,6-trifluoro-5-methyl-2-nitrobenzoylacetate wereadded 11.5 g of acetic anhydride and 4.7 g of triethyl orthoformate, andthe mixture was heated under reflux for 1.5 hours. The reaction solutionwas allowed to cool, and the reagent and the like were distilled off,and toluene was added to the residue for azeotropic distillation. Theresidue was added to 10 ml of ethanol, and a solution of 5.0 g of2-amino-3,5-difluoro-6-(p-methoxybenzylamino)pyridine in 15 ml ofethanol was added dropwise to the mixture in an ice bath and the mixturewas stirred at room temperature for 10 minutes. The solvent wasdistilled off the reaction solution, and the residue was subjected tosilica gel column chromatography to obtain 7.1 g of oil from thefractions eluted by ethyl acetate: hexane, 1:10. To 7.0 g of this oilwere added 10 ml of N,N-dimethylformamide and 2.0 g of potassiumcarbonate, and the mixture was stirred at 70° C. for 30 minutes. To thereaction solution was added ethyl acetate and water, and the organiclayer was separated and dried over magnesium sulfate. The solvent wasdistilled off and ethanol was added to the residue to disperse the solidcontent for collection by filtration to thereby obtain 1.5 g of thetitle compound as a pale yellow powder.

Melting point: 225 to 227° C.

¹ HNMR (CDCl₃) δ;

1.37 (t, J=7 Hz, 3H), 1.68 (d, J=3 Hz, 3H), 3.81 (s, 3H), 4.39 (q, J=7Hz, 2H), 4.45 (s, 2H), 5.29 (brs, 1H), 6.83 (d, J=8 Hz, 2H), 7.17 (d,J=8 Hz, 2H), 7.31 (t, J=9 Hz, 1H), 8.45 (s, 1H)

EXAMPLE 96

Synthesis of ethyl5-amino-6,7-difluoro-1-(3,5-difluoro-6-p-methoxybenzylaminopyridin-2-yl)-8-methyl-1,4-dihydro-4-oxoguinoline-3-carboxylate

To 10 ml of acetic acid solution of 1.7 g of ethyl6,7-difluoro-1-(4,6-difluoro-3-p-methoxybenzylaminopyridin-2-yl)-8-methyl-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylatewas added 1.4 g of iron powder, and the mixture was heated and stirredat 90° C. for 4 hours and 40 minutes. The catalyst in the reactionsolution was removed by filtration, and the solvent in the filtrate wasdistilled off. The residue was subjected to silica gel columnchromatography. The fraction eluted by chloroform:methanol, 10:1 wasconcentrated, and ethanol was added to the residue. The powderprecipitate was collected by filtration to obtain 1.3 g of the titlecompound as a pale brown powder.

Melting point: 150 to 153° C.

¹ HNMR (d₆ -DMSO) δ;

1.24 (t, J=7 Hz, 3H), 1.30 (s, 3H), 3.71 (s, 3H), 4.20 (q, J=7 Hz, 2H),4.33 (dd, J=5 Hz, 12 Hz, 2H), 6.76 (d, J-=8 Hz, 2H), 7.14 (d, J=8 Hz,2H), 7.85 (brs, IH), 7.93 (t, J=10 Hz, 1H), 8.27 (s, 1H)

EXAMPLE 97

Synthesis of5-amino-1-(6-amino-3,5-difluoropyridin-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoguinoline-3-carboxylicacid

To 0.99 g of ethyl5-amino-6,7-difluoro-1-(3,5-difluoro-6-p-methoxybenzylaminopyridin-2-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylatewas added 10 ml of 12N hydrochloric acid, and the mixture was heatedunder reflux for 10 hours. The reaction solution was allowed to cool,and the solid content was collected by filtration. The solid content waswashed with ethanol, and then, with diethylether to obtain 880 mg of thetitle compound as a yellow powder.

Melting point: 250° C. or higher (decomposed)

¹ HNMR (d₆ -DMSO) δ;

1.60 (s, 3H), 6.80 (brs, 2H), 7.96 (t, J=9 Hz, 1H), 8.69 (s, 1H)

REFERENCE EXAMPLE 52

Synthesis of 2-amino-4-bromo-5-chloro-3,6-difluoropyridine

To 20 ml of acetonitrile were added 4.9 g of4-bromo-3-chloro-2,5,6-trifluoropyridine and 4 ml of 25% aqueoussolution of ammonia, and the mixture was stirred at 55° C. for 2 hours.The solvent and the like were distilled off under reduced pressure. 50ml of chloroform was added to the residue, and the solution was washedwith 50 ml of distilled water. The chloroform layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was dispersed in the mixed solution of diisopropylether andn-hexane and collected by filtration to obtain 3.8 g of the titlecompound as pale yellow needle crystals.

REFERENCE EXAMPLE 53

Synthesis of2-amino-4-bromo-5-chloro-3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridine

To 6 ml of N-methylpyrrolidone were added 2.4 g of2-amino-4-bromo-5-chloro-3,6-difluoropyridine and 3.5 g of1,1,3,3-tetramethylbutylamine, and the mixture was stirred at 140° C.for 82 hours and allowed to cool. 50 ml of the mixed solution of benzeneand n-hexane (1:1, v/v) was added, and the solution was washed twicewith 400 ml of distilled water. The organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Thebrown oily residue was subjected to column chromatography (silica gel,30 g; eluent: chloroform:n-hexane, 1:1) to obtain 1.6 g of the titlecompound as a colorless oily residue.

REFERENCE EXAMPLE 54

Synthesis of 2-amino-3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridine

To 10 ml of methanol were added 1.6 g of2-amino-4-bromo-5-chloro-3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridinetogether with 0.47 g of triethylamine and 0.09 g of 10% palladium oncarbon, and the mixture was hydrogenated at room temperature for 39hours. The catalyst was separated by filtration, and the solvent and thelike were distilled off under reduced pressure. To the residue was added50 ml of chloroform, and the mixture was washed with 50 ml of distilledwater. The chloroform layer was dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was subjected tochromatography (silica gel, 25 g; eluent: chloroform) to obtain 0.75 gof 2-amino-3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridine as a palebrown oil, and 0.2 g of2-amino-4-bromo-3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridine as abrown oil.

EXAMPLE 98

Synthesis of ethyl1-[3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 3 ml chloroform solution of ethyl3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.84g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process wasadded 0.75 g of2-amino-3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridine. The solutionwas concentrated under reduced pressure, and to the residue were added0.65 g of anhydrous potassium carbonate and 1.5 ml ofN,N-dimethylformamide, and the mixture was stirred at 90° C. for 1 hourand allowed to cool. The solution was separated by adding 30 ml ofchloroform and 300 ml of distilled water, and the chloroform layer waswashed twice with 300 ml of distilled water, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theprecipitate was collected by filtration and washed with ethanol anddiisopropylether successively to obtain 0.45 g of the title compound asa pale yellow powder.

Melting point: 178 to 180° C.

¹ HNMR (CDCl₃) δ;

0.96 (s, 9H), 1.41 (m, 9H), 1.77 (dd, J=l5 Hz, 22 Hz, 2H), 4.42 (q, J=7Hz, 2H), 4.53 (brs, 1H), 6.44 (dd, J=3 Hz, 9 Hz, l), 7.30 (t, J=9 Hz,1H), 8.30 (t, J=9 Hz, 1H), 8.56 (s, 1H)

EXAMPLE 99

Synthesis of1-(6-amino-3-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 1.2 ml of the mixed solution of 4N hydrochloric acid and acetate(1:1) was added 235 mg of ethyl1-[3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylateand the mixture was heated under reflux for 6 hours with stirring andallowed to cool. The precipitate was collected by filtration and washedwith ethanol to obtain 145 mg of the title compound as a gray powder.

Melting point: 228 to 230° C.

¹ HNMR (d₆ -DMSO) δ;

6.70 (dd, J=3 Hz, 9 Hz, 1H), 7.66 (t, J=9 Hz, 1H), 8.38 (t, J=9 Hz, 1H),8.87 (s, 1H)

EXAMPLE 100

Synthesis of7-(3-aminoazetidin-1-yl)-1-(6-amino-3-fluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 190 mg of N,N-dimethylformamide were added 57 mg of1-(6-amino-3-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 37 mg of 3-aminoazetidine dihydrochloride, and 100 mg ofN-methylpyrrolidine, and the mixture was stirred at 90° C. for 30minutes. After adding 0.2 ml of ethanol, the mixture was allowed tocool, and the precipitate was collected by filtration and washed withethanol and diisopropylether successively to obtain 40 mg of the titlecompound as a colorless powder.

Melting point: 250 to 255° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

3.71 (m, 1H), 4.04 (m, 2H), 4.67 (m, 2H), 6.44 (brs, 2H), 6.62 (dd, J=3Hz, 9 Hz, 1H), 7.61 (d, J=9 Hz, 1H), 7.85 (t, J=l4 Hz, 1H), 8.63 (s, 1H)

EXAMPLE 101

Synthesis of5-amino-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-methylaminoazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To 300 mg of pyridine were added 120 mg of 5-amino-1-(6-amino-3 ,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80mg of 3-methylaminoazetidine diacetate, and 250 mg ofN-methylpyrrolidine, and the mixture was stirred at 100° C. for 10minutes. After adding 5 ml of diethylether, the mixture was stirred andallowed to cool for 1 hour, and decanted. 2 ml of ethanol was added andthe mixture was stirred. The precipitate was collected by filtration andwashed with ethanol and diethylether successively to obtain 72 mg of thetitle compound as a yellow powder.

Melting point: 204 to 213° C.

¹ HNMR (d₆ -DMSO) δ;

2.02 (s, 3H), 4.05 (m, 2H), 4.57 (m, 2H), 6.70 (brs, 2H), 7.48 (brs,1H), 7.89 (t, J=10 Hz, 1H), 8.49 (s, 1H)

EXAMPLE 102

Synthesis of 5-amino-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyaminoazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 300 mg of pyridine were added 120 mg of 5-amino-1- (6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, 80 mg of 3-hydroxyaminoazetidine hydrochloride, and 250 mg ofN-methylpyrrolidine, and the mixture was stirred at 100° C. for 3minutes. After adding 5 ml of diethylether, the mixture was allowed tostand for 1 hour and decanted. 2 ml of ethanol was added and the mixturewas stirred. The precipitate was collected by filtration and washed withethanol and diethylether successively to obtain 64 mg of the titlecompound as a yellow powder.

Melting point: 267 to 290° C. (decomposed)

¹ HNMR (d₆ -DMSO) δ;

4.09 (m, 2H), 4.45 (m, 1H), 4.63 (m, 2H), 5.69 (d, J=6 Hz, 1H), 6.71(brs, 2H), 7.48 (brs, 1H), 7.89 (t, J=10 Hz, 1H), 8.51 (s, 1H)

(1) Antibacterial action

The compounds of the Examples 9, 10, 12 and 39 as described above wereevaluated for their minimum growth inhibitory concentration (MIC, μg/ml)in accordance with the standard method of Japan Chemotherapy Society(Chemotherapy 29(1), 76, 1981) using the standard strains (S. aureus209P, S. epidermidis IFO12293, P. aeruginosa IFO 3445). The results areshown in Table 1. It should be noted that ciprofloxacin, levofloxacin,sparfloxacin and tosufloxacin which are conventional antibacterials werealso evaluated for their minimum growth inhibitory concentration (MIC,μg/ml) for the purpose of comparison. The results are also shown inTable 1.

                  TABLE 1                                                         ______________________________________                                        Compound    S. aureus S. epidermidis                                                                            P. aeruginosa                               ______________________________________                                        Compound of Ex. 9                                                                         <0.013    0.025       0.05                                          Compound of Ex. 10 <0.013 0.025 0.10                                          Compound of Ex. 12 <0.013 <0.013  0.39                                        Compound of Ex. 39 <0.013 0.025 0.05                                          Ciprofloxacin 0.10 0.39  0.20                                                 Levofloxacin 0.10 0.39  0.39                                                  Sparfloxacin 0.10 0.20  0.78                                                  Tosufloxacin 0.05 0.20  0.39                                                ______________________________________                                    

The results shown in Table 1 reveal that the compounds of the presentinvention has excellent antibacterial activities superior to those ofthe conventional antibacterials.

(2) Phototoxicity test

The compounds of the Examples 9, 10, 12 and 39 as described above weresubjected to phototoxicity test by the procedure as described below.

Female ICR mice (5 to 6 week old) were intravenously administered withthe test compound (40 mg/kg/10 ml), and irradiated with UV (320 to 400nm, 1.8 mW/cm² /sec) for 4 hours. Abnormality in the ears was monitoredat 0 hour (immediately after the irradiation) and after 24 and 48 hours.The ear abnormality was evaluated by the following is criteria: noabnormality (0 point), very slight erythema (1 point), well definederythema (2 points), moderate to severe erythema and edema formation (3points). The results are shown in Table 2. Tosufloxacin which is aconventional known antibacterial agent was also tested in a similar wayfor the purpose of comparison. The results are also shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                    0 hour                                                               (point,                                                                      Compound occurrence) 24 hours 48 hours                                      ______________________________________                                        Compound of Ex. 9                                                                         0,     0/3     0,   0/3   0,   0/3                                  Compound of Ex. 10 0, 0/3 0, 0/3 0, 0/3                                       Compound of Ex. 12 0, 0/3 0, 0/3 0, 0/3                                       Compound of Ex. 39 0, 0/3 0, 0/3 0, 0/3                                       Tosufloxacin 1.8, 4/5 0.8, 4/5 0.2 1/5                                      ______________________________________                                    

The results shown in Table 2 demonstrate that the compounds of thepresent invention have very low toxicity.

We claim:
 1. A pyridonecarboxylic acid derivative represented by the following general formula (1) or a salt thereof: ##STR9## wherein R¹ represents a hydrogen atom or a carboxyl protective group; R² represents a hydroxyl group, a lower alkoxy group, or a substituted or unsubstituted amino group; R³ represents a hydrogen atom or a halogen atom; R⁴ represents a hydrogen atom or a halogen atom; R⁵ represents a halogen atom or an optionally substituted saturated cyclic amino group; R⁶ represents a hydrogen atom, a halogen atom, a nitro group, or an optionally protected amino group; X, Y and Z may be the same or different and respectively represent a nitrogen atom, --CH═ or --CR⁷ ═ (wherein R⁷ represents a lower alkyl group, a halogen atom, or a cyano group), with the proviso that at least one of X, Y and Z represent a nitrogen atom, and W represents a nitrogen atom or --CR⁸ ═(wherein R⁸ represents a hydrogen atom, a halogen atom, or a lower alkyl group), and with the proviso that when R³ represents a hydrogen atom, R² represents an amino group, R³ and R⁴ represent a fluorine atom, R⁶ represents a hydrogen atom, X represents a nitrogen atom, Y represents --CR⁷ ═ (wherein R⁷ represents a fluorine atom), Z represents --CH═ , and W is --CR⁸ ═(wherein R⁸ represents a chlorine atom), then R⁵ is not a 3-hydroxyazetidine-1-yl group.
 2. An antibacterial pharmaceutical composition containing the compound of claim 1 or a salt thereof and a pharmaceutically acceptable carrier therefor.
 3. The pyridonecarboxylic acid derivative or a salt thereof claim 1, wherein W is --CR⁸ ═, wherein R⁸ represents hydrogen atom, a halogen atom, or a lower alkyl group.
 4. The pyridonecarboxylic acid derivative or salt thereof of claim 1 or 3, wherein R⁵ is a group represented by the following formula (a) or (b): ##STR10## wherein A represents an oxygen atom, sulfur atom or NR⁹ (wherein R⁹ represents hydrogen atom or a lower alkyl group), e represents a number from 3 to 5, f represents a number from 1 to 3, g represents a number from 0 to 2, J¹, to J² and J³, which may be the same or different from one another, represent a hydrogen atom, hydroxyl group, lower alkyl group, amino lower alkyl group, amino group, lower alkylamino group, lower alkoxy group, or a halogen atom.
 5. The pyridonecarboxylic acid derivative or salt thereof of claim 4, wherein R⁵ is a group represented by formula (a).
 6. The pyridonecarboxylic acid derivative or salt thereof of claim 5, wherein e in the formula (a) is 3 or
 4. 7. The pyridonecarboxylic acid derivative or salt thereof of claim 6, wherein R¹ is a hydrogen atom; R² is an amino group, lower alkylamino group, or a di-lower alkylamino group; R³ is a halogen atom; R⁴ is a halogen atom; R⁶ is hydrogen atom; X is a nitrogen atom; Y and Z are --CH═ or --CR⁷ ═ (wherein R⁷ is a lower alkyl group or a halogen atom); and W is --CR═(wherein R⁸ is a halogen atom or a lower alkyl group).
 8. The pyridonecarboxylic acid derivative or salt thereof of claim 7, wherein R² is amino group; R³ is fluorine atom; R⁴ is a fluorine atom; Y is --CF═; Z is --CH═; W is --CR═(wherein R⁸ is a chlorine atom, bromine atom or a methyl group), and e in formula (a) is
 3. 9. The pyridonecarboxylic acid derivative or salt thereof of claim 1, wherein the compound represented by formula (I) is 1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6-fluro-7-(3-methylaminoazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
 10. A method of treating a person infected with bacteria by administering an pharmaceutically effective amount of the compound of claim 1 to a person in need thereof.
 11. A method of treating an animal infected with bacteria by administering an pharmaceutically effective amount of the compound of claim 1 to an animal in need thereof. 